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Targeting Notch in oncology: the path forward

Nature Reviews Drug Discovery volume 20, pages 125–144 (2021)Cite this article

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Abstract

Notch signalling is involved in many aspects of cancer biology, including angiogenesis, tumour immunity and the maintenance of cancer stem-like cells. In addition, Notch can function as an oncogene and a tumour suppressor in different cancers and in different cell populations within the same tumour. Despite promising preclinical results and early-phase clinical trials, the goal of developing safe, effective, tumour-selective Notch-targeting agents for clinical use remains elusive. However, our continually improving understanding of Notch signalling in specific cancers, individual cancer cases and different cell populations, as well as crosstalk between pathways, is aiding the discovery and development of novel investigational Notch-targeted therapeutics.

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Fig. 1: Overview of Notch signalling, therapeutic targets and pharmacological agents.
Fig. 2: Intratumoural heterogeneity of Notch function.
Fig. 3: Notch roles in tumour angiogenesis.
Fig. 4: Ligand-independent Notch activation by the TCR and its modulation by adenosine in T cells.
Fig. 5: Notch-mediated crosstalk between BLBCCs and TAMs.

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References

  1. Morgan, T. H. The theory of the gene. Am. Naturalist. 609, 513–544 (1917).

    Google Scholar 

  2. Artavanis-Tsakonas, S., Muskavitch, M. A. & Yedvobnick, B. Molecular cloning of Notch, a locus affecting neurogenesis in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 80, 1977–1981 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Wharton, K. A., Johansen, K. M., Xu, T. & Artavanis-Tsakonas, S. Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF- like repeats. Cell 43, 567–581 (1985).

    CAS  PubMed  Google Scholar 

  4. Yochem, J., Weston, K. & Greenwald, I. The Caenorhabditis elegans lin-12 gene encodes a transmembrane protein with overall similarity to Drosophila Notch. Nature 335, 547–550 (1988).

    CAS  PubMed  Google Scholar 

  5. Yochem, J. & Greenwald, I. glp-1 and lin-12, genes implicated in distinct cell-cell interactions in C. elegans, encode similar transmembrane proteins. Cell 58, 553–563 (1989).

    CAS  PubMed  Google Scholar 

  6. Kopan, R. Notch signaling. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a011213 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kopan, R. & Ilagan, M. X. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137, 216–233 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ladi, E. et al. The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. J. Cell Biol. 170, 983–992 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Andersson, E. R. & Lendahl, U. Therapeutic modulation of Notch signalling–are we there yet? Nat. Rev. Drug Discov. 13, 357–378 (2014). This article is a comprehensive review of therapeutic targeting of Notch signalling in multiple indications.

    CAS  PubMed  Google Scholar 

  10. Kovall, R. A., Gebelein, B., Sprinzak, D. & Kopan, R. The canonical notch signaling pathway: structural and biochemical insights into shape, sugar, and force. Dev. Cell 41, 228–241 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Ellisen, L. W. et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66, 649–661 (1991). This is the first demonstration of oncogenic activity of NOTCH1 in humans.

    CAS  PubMed  Google Scholar 

  12. Weng, A. P. et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306, 269–271 (2004).

    CAS  PubMed  Google Scholar 

  13. Weng, A. P. et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 20, 2096–2109 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Fabbri, G. et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J. Exp. Med. 208, 1389–1401 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Rossi, D. et al. The coding genome of splenic marginal zone lymphoma: Activation of NOTCH2 and other pathways regulating marginal zone development. J. Exp. Med. 209, 1537–1551 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Robinson, D. R. et al. Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer. Nat. Med. 17, 1646–1651 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Dang, T. P. et al. Chromosome 19 translocation, overexpression of Notch3, and human lung cancer. J. Natl Cancer Inst. 92, 1355–1357 (2000).

    CAS  PubMed  Google Scholar 

  18. Ho, A. S. et al. Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma. J. Clin. Invest. 129, 4276–4289 (2019).

    PubMed  PubMed Central  Google Scholar 

  19. Espinoza, I. & Miele, L. Deadly crosstalk: Notch signaling at the intersection of EMT and cancer stem cells. Cancer Lett. 341, 41–45 (2013).

    CAS  PubMed  Google Scholar 

  20. Espinoza, I., Pochampally, R., Xing, F., Watabe, K. & Miele, L. Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. OncoTargets Ther. 6, 1249–1259 (2013).

    Google Scholar 

  21. Sosa Iglesias, V., Giuranno, L., Dubois, L. J., Theys, J. & Vooijs, M. Drug resistance in non-small cell lung cancer: a potential for NOTCH targeting? Front. Oncol. 8, 267 (2018).

    PubMed  PubMed Central  Google Scholar 

  22. Meurette, O. & Mehlen, P. Notch signaling in the tumor microenvironment. Cancer Cell 34, 536–548 (2018).

    CAS  PubMed  Google Scholar 

  23. Mollen, E. W. J. et al. Moving breast cancer therapy up a notch. Front. Oncol. 8, 518 (2018).

    PubMed  PubMed Central  Google Scholar 

  24. Arruga, F., Vaisitti, T. & Deaglio, S. The NOTCH pathway and its mutations in mature B cell malignancies. Front. Oncol. 8, 550 (2018).

    PubMed  PubMed Central  Google Scholar 

  25. Saygin, C., Matei, D., Majeti, R., Reizes, O. & Lathia, J. D. Targeting cancer stemness in the clinic: from hype to hope. Cell Stem Cell 24, 25–40 (2019).

    CAS  PubMed  Google Scholar 

  26. Ceccarelli, S. et al. Notch3 targeting: a novel weapon against ovarian cancer stem cells. Stem Cell Int. 2019, 6264931 (2019).

    Google Scholar 

  27. Xiu, M. X. & Liu, Y. M. The role of oncogenic Notch2 signaling in cancer: a novel therapeutic target. Am. J. Cancer Res. 9, 837–854 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Giuli, M. V., Giuliani, E., Screpanti, I., Bellavia, D. & Checquolo, S. Notch signaling activation as a hallmark for triple-negative breast cancer subtype. J. Oncol. 2019, 8707053 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Gersey, Z. et al. Therapeutic targeting of the notch pathway in glioblastoma multiforme. World Neurosurg. 131, 252–263.e252 (2019).

    PubMed  Google Scholar 

  30. Takebe, N. et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat. Rev. Clin. Oncol. https://doi.org/10.1038/nrclinonc.2015.61 (2015). This review covers the challenges and opportunities in targeting master developmental pathways in cancer stem cells.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Bray, S. J. Notch signalling in context. Nat. Rev. Mol. Cell Biol. 17, 722–735 (2016).

    CAS  PubMed  Google Scholar 

  32. Espinoza, I. & Miele, L. Notch inhibitors for cancer treatment. Pharmacol Ther. https://doi.org/10.1016/j.pharmthera.2013.02.003 (2013).

  33. Carrieri, F. A. et al. CDK1 and CDK2 regulate NICD1 turnover and the periodicity of the segmentation clock. EMBO Rep. 20, e46436 (2019).

    PubMed  PubMed Central  Google Scholar 

  34. Aster, J. C., Pear, W. S. & Blacklow, S. C. The varied roles of notch in cancer. Annu. Rev. Pathol. 12, 245–275 (2017). This article provides a comprehensive review of the multiple roles of Notch signalling in cancer.

    CAS  PubMed  Google Scholar 

  35. Vinson, K. E., George, D. C., Fender, A. W., Bertrand, F. E. & Sigounas, G. The Notch pathway in colorectal cancer. Int. J. Cancer 138, 1835–1842 (2016).

    CAS  PubMed  Google Scholar 

  36. Kwon, O. J. et al. Notch promotes tumor metastasis in a prostate-specific Pten-null mouse model. J. Clin. Invest. 126, 2626–2641 (2016).

    PubMed  PubMed Central  Google Scholar 

  37. Bazzoni, R. & Bentivegna, A. Role of Notch signaling pathway in glioblastoma pathogenesis. Cancers https://doi.org/10.3390/cancers11030292 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Tamagnone, L., Zacchigna, S. & Rehman, M. Taming the Notch transcriptional regulator for cancer therapy. Molecules https://doi.org/10.3390/molecules23020431 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Thurston, G. & Kitajewski, J. VEGF and Delta-Notch: interacting signalling pathways in tumour angiogenesis. Br. J. Cancer 99, 1204–1209 (2008). This article describes the interplay between VEGF and Notch signalling in tumour angiogenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Radtke, F. & Raj, K. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat. Rev. Cancer 3, 756–767 (2003).

    CAS  PubMed  Google Scholar 

  41. Ranganathan, P., Weaver, K. L. & Capobianco, A. J. Notch signalling in solid tumours: a little bit of everything but not all the time. Nat. Rev. Cancer 11, 338–351 (2011).

    CAS  PubMed  Google Scholar 

  42. Nguyen, B. C. et al. Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev. 20, 1028–1042 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Koch, U. & Radtke, F. Notch and cancer: a double-edged sword. Cell. Mol. Life Sci. 64, 2746–2762 (2007).

    CAS  PubMed  Google Scholar 

  44. Lowell, S., Jones, P., Le Roux, I., Dunne, J. & Watt, F. M. Stimulation of human epidermal differentiation by Delta–Notch signalling at the boundaries of stem-cell clusters. Curr. Biol. 10, 491–500 (2000).

    CAS  PubMed  Google Scholar 

  45. Rangarajan, A. et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 20, 3427–3436 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Klinakis, A. et al. A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature 473, 230–233 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Zage, P. E. et al. Notch pathway activation induces neuroblastoma tumor cell growth arrest. Pediatr. Blood Cancer 58, 682–689 (2012).

    PubMed  Google Scholar 

  48. Hernandez Tejada, F. N., Galvez Silva, J. R. & Zweidler-McKay, P. A. The challenge of targeting notch in hematologic malignancies. Front. Pediatr. 2, 54 (2014).

    PubMed  PubMed Central  Google Scholar 

  49. Viatour, P. et al. Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J. Exp. Med. 208, 1963–1976 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ye, Y. C. et al. NOTCH Signaling via WNT regulates the proliferation of alternative, CCR2-independent tumor-associated macrophages in hepatocellular carcinoma. Cancer Res. 79, 4160–4172 (2019).

    CAS  PubMed  Google Scholar 

  51. Fang, S. et al. Lymphoid enhancer-binding factor-1 promotes stemness and poor differentiation of hepatocellular carcinoma by directly activating the NOTCH pathway. Oncogene 38, 4061–4074 (2019).

    CAS  PubMed  Google Scholar 

  52. Fukusumi, T. & Califano, J. A. The NOTCH pathway in head and neck squamous cell carcinoma. J. Dent. Res. 97, 645–653 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Yokoyama, A. et al. Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature 565, 312–317 (2019).

    CAS  PubMed  Google Scholar 

  54. Lim, J. S. et al. Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer. Nature 545, 360–364 (2017). This study is the first demonstration that Notch can have tumour-suppressive and oncogenic functions in different, interacting cell populations in the same tumour.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Clevers, H. The cancer stem cell: premises, promises and challenges. Nat. Med. 17, 313–319 (2011).

    CAS  PubMed  Google Scholar 

  56. Batlle, E. & Clevers, H. Cancer stem cells revisited. Nat. Med. 23, 1124–1134 (2017).

    CAS  PubMed  Google Scholar 

  57. Fan, X. et al. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res. 66, 7445–7452 (2006).

    CAS  PubMed  Google Scholar 

  58. Armstrong, F. et al. NOTCH is a key regulator of human T-cell acute leukemia initiating cell activity. Blood 113, 1730–1740 (2009).

    CAS  PubMed  Google Scholar 

  59. Sikandar, S. S. et al. NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer. Cancer Res. 70, 1469–1478 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Harrison, H., Farnie, G., Brennan, K. R. & Clarke, R. B. Breast cancer stem cells: something out of notching? Cancer Res. 70, 8973–8976 (2010).

    CAS  PubMed  Google Scholar 

  61. Hassan, K. A. et al. Notch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma. Clin. Cancer Res. 19, 1972–1980 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Crabtree, J. S. & Miele, L. Breast cancer stem cells. Biomedicines https://doi.org/10.3390/biomedicines6030077 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Harrison, H. et al. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res. 70, 709–718 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Robinson, D. R. et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat. Genet. 45, 1446–1451 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Toy, W. et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat. Genet. 45, 1439–1445 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Fuqua, S. A., Gu, G. & Rechoum, Y. Estrogen receptor (ER) alpha mutations in breast cancer: hidden in plain sight. Breast Cancer Res. Treat. 144, 11–19 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Gelsomino, L. et al. Mutations in the estrogen receptor alpha hormone binding domain promote stem cell phenotype through notch activation in breast cancer cell lines. Cancer Lett. 428, 12–20 (2018).

    CAS  PubMed  Google Scholar 

  68. Hirata, N. et al. Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation. Nat. Commun. 5, 4806 (2014). This study suggests a potentially druggable, ligand-independent Notch activation mechanism in breast cancer stem cells.

    CAS  PubMed  Google Scholar 

  69. Mao, J. et al. ShRNA targeting Notch1 sensitizes breast cancer stem cell to paclitaxel. Int. J. Biochem. Cell Biol. 45, 1064–1073 (2013).

    CAS  PubMed  Google Scholar 

  70. Bhola, N. E. et al. Treatment of triple-negative breast cancer with TORC1/2 inhibitors sustains a drug-resistant and notch-dependent cancer stem cell population. Cancer Res. 76, 440–452 (2016). This study implicates Notch-dependent CSCs in mTOR complex 1/2 resistance in TNBC.

    CAS  PubMed  Google Scholar 

  71. Pandya, K. et al. Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence. Br. J. Cancer 105, 796–806 (2011). This study implicates Notch signalling in trastuzumab resistance.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Shah, D. et al. Inhibition of HER2 increases JAGGED1-dependent breast cancer stem cells: role for membrane JAGGED1. Clin. Cancer Res. 24, 4566–4578 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Baker, A. et al. Notch-1-PTEN-ERK1/2 signaling axis promotes HER2+ breast cancer cell proliferation and stem cell survival. Oncogene 37, 4489–4504 (2018).

    CAS  PubMed  Google Scholar 

  74. Luo, H. et al. Differentiation-inducing therapeutic effect of Notch inhibition in reversing malignant transformation of liver normal stem cells via MET. Oncotarget 9, 18885–18895 (2018).

    PubMed  PubMed Central  Google Scholar 

  75. Man, J. et al. Hypoxic induction of vasorin regulates Notch1 turnover to maintain glioma stem-like cells. Cell Stem Cell 22, 104–118 e106 (2018).

    CAS  PubMed  Google Scholar 

  76. Tsao, P. N. et al. Gamma-secretase activation of notch signaling regulates the balance of proximal and distal fates in progenitor cells of the developing lung. J. Biol. Chem. 283, 29532–29544 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Westhoff, B. et al. Alterations of the Notch pathway in lung cancer. Proc. Natl Acad. Sci. USA 106, 22293–22298 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Eliasz, S. et al. Notch-1 stimulates survival of lung adenocarcinoma cells during hypoxia by activating the IGF-1R pathway. Oncogene 29, 2488–2498 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Chen, Y. et al. Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung. Cancer Res. 67, 7954–7959 (2007).

    CAS  PubMed  Google Scholar 

  80. Arasada, R. R., Amann, J. M., Rahman, M. A., Huppert, S. S. & Carbone, D. P. EGFR blockade enriches for lung cancer stem-like cells through Notch3-dependent signaling. Cancer Res. 74, 5572–5584 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Arasada, R. R. et al. Notch3-dependent beta-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC. Nat. Commun. 9, 3198 (2018). This study supports a novel non-canonical function of NOTCH3 via β-catenin signalling in TKI resistance in NSCLC.

    PubMed  PubMed Central  Google Scholar 

  82. Weis, S. M. & Cheresh, D. A. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat. Med. 17, 1359–1370 (2011).

    CAS  PubMed  Google Scholar 

  83. Pitulescu, M. E. et al. Dll4 and Notch signalling couples sprouting angiogenesis and artery formation. Nat. Cell Biol. 19, 915–927 (2017).

    CAS  PubMed  Google Scholar 

  84. Ridgway, J. et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444, 1083–1087 (2006).

    CAS  PubMed  Google Scholar 

  85. Noguera-Troise, I. et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Novartis. Found. Symp. 283, 106–120 (2007).

    CAS  PubMed  Google Scholar 

  86. Jia, X. et al. A humanized anti-DLL4 antibody promotes dysfunctional angiogenesis and inhibits breast tumor growth. Sci. Rep. 6, 27985 (2016).

    PubMed  PubMed Central  Google Scholar 

  87. Chiorean, E. G. et al. A phase I first-in-human study of enoticumab (REGN421), a fully human delta-like ligand 4 (Dll4) monoclonal antibody in patients with advanced solid tumors. Clin. Cancer Res. 21, 2695–2703 (2015).

    CAS  PubMed  Google Scholar 

  88. Rizzo, P. et al. The role of notch in the cardiovascular system: potential adverse effects of investigational notch inhibitors. Front. Oncol. 4, 384 (2014).

    PubMed  Google Scholar 

  89. Yan, M. et al. Chronic DLL4 blockade induces vascular neoplasms. Nature 463, E6–E7 (2010).

    CAS  PubMed  Google Scholar 

  90. Liu, Z. et al. Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice. J. Clin. Invest. 121, 800–808 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Kangsamaksin, T. et al. NOTCH decoys that selectively block DLL/NOTCH or JAG/NOTCH disrupt angiogenesis by unique mechanisms to inhibit tumor growth. Cancer Discov. 5, 182–197 (2015).

    CAS  PubMed  Google Scholar 

  92. Ayaz, F. & Osborne, B. A. Non-canonical notch signaling in cancer and immunity. Front. Oncol. 4, 345 (2014). This is a comprehensive review of non-canonical Notch signalling.

    PubMed  PubMed Central  Google Scholar 

  93. Minter, L. M. & Osborne, B. A. Canonical and non-canonical Notch signaling in CD4+ T cells. Curr. Top. Microbiol. Immunol. 360, 99–114 (2012).

    CAS  PubMed  Google Scholar 

  94. Hossain, F. et al. Notch signaling in myeloid cells as a regulator of tumor immune responses. Front. Immunol. 9, 1288 (2018).

    PubMed  PubMed Central  Google Scholar 

  95. Vijayaraghavan, J. & Osborne, B. A. Notch and T Cell Function - a complex tale. Adv. Exp. Med. Biol. 1066, 339–354 (2018).

    CAS  PubMed  Google Scholar 

  96. Janghorban, M., Xin, L., Rosen, J. M. & Zhang, X. H. Notch signaling as a regulator of the tumor immune response: to target or not to target? Front. Immunol. 9, 1649 (2018).

    PubMed  PubMed Central  Google Scholar 

  97. Tsukumo, S. I. & Yasutomo, K. Regulation of CD8+ T cells and antitumor immunity by notch signaling. Front. Immunol. 9, 101 (2018). Tsukumo and Yasutomo (2018), Cho et al. (2009), Maekawa et al. (2008) and Sugimoto et al. (2010) describe the role of Notch signalling in promoting CD8+ T cell-mediated tumour immunity.

    PubMed  PubMed Central  Google Scholar 

  98. Cho, O. H. et al. Notch regulates cytolytic effector function in CD8+ T cells. J. Immunol. 182, 3380–3389 (2009).

    CAS  PubMed  Google Scholar 

  99. Maekawa, Y. et al. Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity. Nat. Immunol. 9, 1140–1147 (2008).

    CAS  PubMed  Google Scholar 

  100. Sugimoto, K. et al. Notch2 signaling is required for potent antitumor immunity in vivo. J. Immunol. 184, 4673–4678 (2010).

    CAS  PubMed  Google Scholar 

  101. Kijima, M. et al. Jagged1 suppresses collagen-induced arthritis by indirectly providing a negative signal in CD8+ T cells. J. Immunol. 182, 3566–3572 (2009).

    CAS  PubMed  Google Scholar 

  102. Huang, Y. et al. Resuscitating cancer immunosurveillance: selective stimulation of DLL1-Notch signaling in T cells rescues T-cell function and inhibits tumor growth. Cancer Res. 71, 6122–6131 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Biktasova, A. K. et al. Multivalent forms of the notch ligand DLL-1 enhance antitumor T-cell immunity in lung cancer and improve efficacy of EGFR-targeted therapy. Cancer Res. 75, 4728–4741 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Kondo, T. et al. Notch-mediated conversion of activated T cells into stem cell memory-like T cells for adoptive immunotherapy. Nat. Commun. 8, 15338 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Steinbuck, M. P. & Winandy, S. A review of notch processing with new insights into ligand-independent notch signaling in T-cells. Front. Immunol. 9, 1230 (2018). Steinbuck and Winandy (2018) and Steinbuck et al. (2018) describe endosomal, ligand-independent Notch activation in the context of T cell activation.

    PubMed  PubMed Central  Google Scholar 

  106. Steinbuck, M. P., Arakcheeva, K. & Winandy, S. Novel TCR-mediated mechanisms of notch activation and signaling. J. Immunol. 200, 997–1007 (2018).

    CAS  PubMed  Google Scholar 

  107. Sorrentino, C. et al. Adenosine A2A receptor stimulation inhibits TCR-induced Notch1 activation in CD8+T-cells. Front. Immunol. 10, 162 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Congreve, M., Brown, G. A., Borodovsky, A. & Lamb, M. L. Targeting adenosine A2A receptor antagonism for treatment of cancer. Expert Opin. Drug Discov. 13, 997–1003 (2018).

    CAS  PubMed  Google Scholar 

  109. Sierra, R. A. et al. Rescue of notch-1 signaling in antigen-specific CD8+ T cells overcomes tumor-induced T-cell suppression and enhances immunotherapy in cancer. Cancer Immunol. Res. 2, 800–811 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Roybal, K. T. et al. Engineering T cells with customized therapeutic response programs using synthetic notch receptors. Cell 167, 419–432 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Cho, J. H. et al. Engineering Axl specific CAR and SynNotch receptor for cancer therapy. Sci. Rep. 8, 3846 (2018). This study demonstrates the feasibility of the synNotch receptor approach in adoptive cell therapy for cancer.

    PubMed  PubMed Central  Google Scholar 

  112. Peng, D. et al. Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH Cross-talk signaling. Cancer Res. 76, 3156–3165 (2016). Peng et al. (2016) and Shen et al. (2017) describe Notch-mediated crosstalk between stroma and breast cancer stem cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Shen, Q. et al. Notch shapes the innate immunophenotype in breast cancer. Cancer Discov. 7, 1320–1335 (2017).

    CAS  PubMed  Google Scholar 

  114. Yeong, J., Thike, A. A., Tan, P. H. & Iqbal, J. Identifying progression predictors of breast ductal carcinoma in situ. J. Clin. Pathol. 70, 102–108 (2017).

    CAS  PubMed  Google Scholar 

  115. Strell, C. et al. Impact of epithelial-stromal interactions on peritumoral fibroblasts in ductal carcinoma in situ. J. Natl Cancer Inst. 111, 983–995 (2019).

    PubMed  PubMed Central  Google Scholar 

  116. Sierra, R. A. et al. Anti-jagged immunotherapy inhibits MDSCs and overcomes tumor-induced tolerance. Cancer Res. 77, 5628–5638 (2017). This study supports the potential of Jagged 1 as a therapeutic target in cancer immunotherapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Santagata, S. et al. JAGGED1 expression is associated with prostate cancer metastasis and recurrence. Cancer Res. 64, 6854–6857 (2004).

    CAS  PubMed  Google Scholar 

  118. Zhu, H., Zhou, X., Redfield, S., Lewin, J. & Miele, L. Elevated Jagged-1 and Notch-1 expression in high grade and metastatic prostate cancers. Am. J. Transl Res. 5, 368–378 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Sethi, N., Dai, X., Winter, C. G. & Kang, Y. Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 19, 192–205 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Zheng, H. et al. Therapeutic antibody targeting tumor- and osteoblastic niche-derived jagged1 sensitizes bone metastasis to chemotherapy. Cancer Cell 32, 731–747 (2017). Sethi et al. (2011) and Zheng et al. (2017) support the potential of Jagged 1 as a therapeutic target in metastasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Houde, C. et al. Over-expression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines. Blood 104, 3697–3704 (2004).

    CAS  PubMed  Google Scholar 

  122. Colombo, M. et al. Multiple myeloma-derived Jagged ligands increases autocrine and paracrine interleukin-6 expression in bone marrow niche. Oncotarget 7, 56013–56029 (2016).

    PubMed  PubMed Central  Google Scholar 

  123. Colombo, M. et al. Multiple myeloma exploits Jagged1 and Jagged2 to promote intrinsic and bone marrow-dependent drug resistance. Haematologica https://doi.org/10.3324/haematol.2019.221077 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Leontovich, A. A. et al. NOTCH3 expression is linked to breast cancer seeding and distant metastasis. Breast Cancer Res. 20, 105 (2018).

    PubMed  PubMed Central  Google Scholar 

  125. Choy, L. et al. Constitutive NOTCH3 signaling promotes the growth of basal breast cancers. Cancer Res. 77, 1439–1452 (2017).

    CAS  PubMed  Google Scholar 

  126. Imbimbo, B. P. et al. Therapeutic intervention for Alzheimer’s disease with gamma-secretase inhibitors: still a viable option? Expert Opin. Invest. Drugs 20, 325–341 (2011).

    CAS  Google Scholar 

  127. Ran, Y. et al. gamma-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct. EMBO Mol. Med. 9, 950–966 (2017). This study highlights the different pharmacological properties and anti-CSC activity of different classes of investigational GSIs.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Schott, A. F. et al. Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. Clin. Cancer Res. 19, 1512–1524 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Riccio, O. et al. Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep. 9, 377–383 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Samon, J. B. et al. Preclinical analysis of the gamma-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia. Mol. Cancer Ther. 11, 1565–1575 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Yun, J. et al. Crosstalk between PKCalpha and Notch-4 in endocrine-resistant breast cancer cells. Oncogenesis 2, e60 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Dumortier, A. et al. Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of notch signaling in the murine skin. PloS ONE 5, e9258 (2010).

    PubMed  PubMed Central  Google Scholar 

  133. Papayannidis, C. et al. A phase 1 study of the novel gamma-secretase inhibitor PF-03084014 in patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Blood Cancer J. 5, e350 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Locatelli, M. A. et al. Phase I study of the gamma secretase inhibitor PF-03084014 in combination with docetaxel in patients with advanced triple-negative breast cancer. Oncotarget 8, 2320–2328 (2017).

    PubMed  Google Scholar 

  135. Kummar, S. et al. Clinical activity of the gamma-secretase inhibitor PF-03084014 in Adults with desmoid tumors (aggressive fibromatosis). J. Clin. Oncol. 35, 1561–1569 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Villalobos, V. M. et al. Long-term follow-up of desmoid fibromatosis treated with PF-03084014, an oral gamma secretase inhibitor. Ann. Surg. Oncol. 25, 768–775 (2018).

    PubMed  Google Scholar 

  137. Takahashi, T., Prensner, J. R., Robson, C. D., Janeway, K. A. & Weigel, B. J. Safety and efficacy of gamma-secretase inhibitor nirogacestat (PF-03084014) in desmoid tumor: report of four pediatric/young adult cases. Pediatr Blood Cancer https://doi.org/10.1002/pbc.28636 (2020).

    Article  PubMed  Google Scholar 

  138. Morgan, K. M. et al. Gamma secretase inhibition by BMS-906024 enhances efficacy of paclitaxel in lung adenocarcinoma. Mol. Cancer Ther. 16, 2759–2769 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Massard, C. et al. First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer. Ann. Oncol. 29, 1911–1917 (2018).

    CAS  PubMed  Google Scholar 

  140. Moss, M. L. & Minond, D. Recent advances in ADAM17 research: a promising target for cancer and inflammation. Mediators Inflamm. 2017, 9673537 (2017).

    PubMed  PubMed Central  Google Scholar 

  141. Malapeira, J., Esselens, C., Bech-Serra, J. J., Canals, F. & Arribas, J. ADAM17 (TACE) regulates TGFbeta signaling through the cleavage of vasorin. Oncogene 30, 1912–1922 (2011).

    CAS  PubMed  Google Scholar 

  142. Li, D. D. et al. A novel inhibitor of ADAM17 sensitizes colorectal cancer cells to 5-Fluorouracil by reversing Notch and epithelial-mesenchymal transition in vitro and in vivo. Cell Prolif. 51, e12480 (2018).

    PubMed  PubMed Central  Google Scholar 

  143. Wu, Y. et al. Therapeutic antibody targeting of individual Notch receptors. Nature 464, 1052–1057 (2010).

    CAS  PubMed  Google Scholar 

  144. Aste-Amezaga, M. et al. Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors. PLoS ONE 5, e9094 (2010).

    PubMed  PubMed Central  Google Scholar 

  145. Agnusdei, V. et al. Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts. Leukemia 28, 278–288 (2014).

    CAS  PubMed  Google Scholar 

  146. Agnusdei, V. et al. Dissecting molecular mechanisms of resistance to Notch1-targeted therapy in T-cell acute lymphoblastic leukemia xenografts. Haematologica https://doi.org/10.3324/haematol.2019.217687 (2019).

    Article  PubMed  Google Scholar 

  147. Sharma, A. et al. A novel monoclonal antibody against notch1 targets leukemia-associated mutant notch1 and depletes therapy resistant cancer stem cells in solid tumors. Sci. Rep. 5, 11012 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Bernasconi-Elias, P. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Proia, T. et al. 23814, an inhibitory antibody of ligand-mediated Notch1 activation, modulates angiogenesis and inhibits tumor growth without gastrointestinal toxicity. Mol. Cancer Ther. 14, 1858–1867 (2015).

    CAS  PubMed  Google Scholar 

  150. Yen, W. C. et al. Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clin. Cancer Res. 21, 2084–2095 (2015).

    CAS  PubMed  Google Scholar 

  151. Smith, D. C. et al. A phase 1 dose escalation and expansion study of tarextumab (OMP-59R5) in patients with solid tumors. Invest. N. Drugs 37, 722–730 (2019).

    CAS  Google Scholar 

  152. Hu, Z. I. et al. A randomized phase II trial of nab-paclitaxel and gemcitabine with tarextumab or placebo in patients with untreated metastatic pancreatic cancer. Cancer Med. 8, 5148–5157 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Hu, S. et al. Antagonism of EGFR and Notch limits resistance to EGFR inhibitors and radiation by decreasing tumor-initiating cell frequency. Sci. Transl Med. https://doi.org/10.1126/scitranslmed.aag0339 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Rosen, L. S. et al. A phase I, dose-escalation study of PF-06650808, an anti-Notch3 antibody-drug conjugate, in patients with breast cancer and other advanced solid tumors. Invest. New Drugs https://doi.org/10.1007/s10637-019-00754-y (2019).

    Article  PubMed  Google Scholar 

  155. Filipovic, A. et al. Anti-nicastrin monoclonal antibodies elicit pleiotropic anti-tumour pharmacological effects in invasive breast cancer cells. Breast Cancer Res. Treat. 148, 455–462 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Smith, D. C. et al. A phase I dose escalation and expansion study of the anticancer stem cell agent demcizumab (anti-DLL4) in patients with previously treated solid tumors. Clin. Cancer Res. 20, 6295–6303 (2014).

    CAS  PubMed  Google Scholar 

  157. McKeage, M. J. et al. Phase IB trial of the anti-cancer stem cell DLL4-binding agent demcizumab with pemetrexed and carboplatin as first-line treatment of metastatic non-squamous NSCLC. Target. Oncol. 13, 89–98 (2018).

    PubMed  Google Scholar 

  158. Coleman, R. L. et al. Demcizumab combined with paclitaxel for platinum-resistant ovarian, primary peritoneal, and fallopian tube cancer: the SIERRA open-label phase Ib trial. Gynecol. Oncol. https://doi.org/10.1016/j.ygyno.2020.01.042 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Huang, J. et al. Dll4 inhibition plus aflibercept markedly reduces ovarian tumor growth. Mol. Cancer Ther. 15, 1344–1352 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Jimeno, A. et al. A first-in-human phase 1a study of the bispecific anti-DLL4/anti-VEGF antibody navicixizumab (OMP-305B83) in patients with previously treated solid tumors. Invest. N. Drugs 37, 461–472 (2019).

    CAS  Google Scholar 

  161. Lafkas, D. et al. Therapeutic antibodies reveal notch control of transdifferentiation in the adult lung. Nature 528, 127–131 (2015).

    CAS  PubMed  Google Scholar 

  162. Pandya, K. et al. PKCalpha attenuates jagged-1-mediated notch signaling in ErbB-2-positive breast cancer to reverse trastuzumab resistance. Clin. Cancer Res. 22, 175–186 (2016).

    CAS  PubMed  Google Scholar 

  163. Saunders, L. R. et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci. Transl Med. 7, 302ra136 (2015).

    PubMed  PubMed Central  Google Scholar 

  164. Morgensztern, D. et al. Efficacy and safety of rovalpituzumab tesirine in third-line and beyond patients with DLL3-expressing, relapsed/refractory small-cell lung cancer: results from the phase II TRINITY study. Clin. Cancer Res. 25, 6958–6966 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Crabtree, J. S., Singleton, C. S. & Miele, L. Notch signaling in neuroendocrine tumors. Front. Oncol. 6, 94 (2016).

    PubMed  PubMed Central  Google Scholar 

  166. Owen, D. H. et al. DLL3: an emerging target in small cell lung cancer. J. Hematol. Oncol. 12, 61 (2019).

    PubMed  PubMed Central  Google Scholar 

  167. Golde, T. E., Koo, E. H., Felsenstein, K. M., Osborne, B. A. & Miele, L. gamma-Secretase inhibitors and modulators. Biochim. Biophys. Acta 1828, 2898–2907 (2013).

    CAS  PubMed  Google Scholar 

  168. Habets, R. A. et al. Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition. Sci. Transl Med. https://doi.org/10.1126/scitranslmed.aau6246 (2019).

    Article  PubMed  Google Scholar 

  169. Borgegard, T. et al. Alzheimer’s disease: presenilin 2-sparing gamma-secretase inhibition is a tolerable Abeta peptide-lowering strategy. J. Neurosci. 32, 17297–17305 (2012).

    PubMed  PubMed Central  Google Scholar 

  170. Bursavich, M. G., Harrison, B. A. & Blain, J. F. Gamma secretase modulators: new Alzheimer’s drugs on the horizon? J. Med. Chem. 59, 7389–7409 (2016).

    CAS  PubMed  Google Scholar 

  171. Wagner, S. L. et al. Pharmacological and toxicological properties of the potent oral gamma-secretase modulator BPN-15606. J. Pharmacol. Exp. Ther. 362, 31–44 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Kounnas, M. Z., Lane-Donovan, C., Nowakowski, D. W., Herz, J. & Comer, W. T. NGP 555, a gamma-secretase modulator, lowers the amyloid biomarker, Abeta42, in cerebrospinal fluid while preventing Alzheimer’s disease cognitive decline in rodents. Alzheimers Dement. 3, 65–73 (2017).

    Google Scholar 

  173. Kukar, T. L. et al. Substrate-targeting gamma-secretase modulators. Nature 453, 925–929 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Kang, M. S. et al. Modulation of lipid kinase PI4KIIalpha activity and lipid raft association of presenilin 1 underlies gamma-secretase inhibition by ginsenoside (20S)-Rg3. J. Biol. Chem. 288, 20868–20882 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Platonova, N. et al. Identification of small molecules uncoupling the Notch::Jagged interaction through an integrated high-throughput screening. PLoS ONE 12, e0182640 (2017).

    PubMed  PubMed Central  Google Scholar 

  176. Gangrade, A. et al. Preferential inhibition of Wnt/beta-catenin signaling by novel benzimidazole compounds in triple-negative breast cancer. Int. J. Mol. Sci. https://doi.org/10.3390/ijms19051524 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Perron, A. et al. Small-molecule screening yields a compound that inhibits the cancer-associated transcription factor Hes1 via the PHB2 chaperone. J. Biol. Chem. 293, 8285–8294 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Urech-Varenne, C., Radtke, F. & Heinis, C. Phage selection of bicyclic peptide ligands of the Notch1 receptor. ChemMedChem 10, 1754–1761 (2015).

    CAS  PubMed  Google Scholar 

  179. Moellering, R. E. et al. Direct inhibition of the NOTCH transcription factor complex. Nature 462, 182–188 (2009). This study is the first demonstration that the Notch transcriptional complex is potentially druggable.

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Opacak-Bernardi, T., Ryu, J. S. & Raucher, D. Effects of cell penetrating Notch inhibitory peptide conjugated to elastin-like polypeptide on glioblastoma cells. J. Drug Target. 25, 523–531 (2017).

    CAS  PubMed  Google Scholar 

  181. Ding, W. et al. Effect of lenalidomide on the human gastric cancer cell line SGC7901/vincristine Notch signaling. J. Cancer Res. Ther. 14, S237–S242 (2018).

    CAS  PubMed  Google Scholar 

  182. Pinazza, M. et al. Histone deacetylase 6 controls Notch3 trafficking and degradation in T-cell acute lymphoblastic leukemia cells. Oncogene 37, 3839–3851 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Zhong, L. et al. Histone deacetylase 5 promotes the proliferation and invasion of lung cancer cells. Oncol. Rep. 40, 2224–2232 (2018).

    CAS  PubMed  Google Scholar 

  184. Granit, R. Z. et al. Regulation of cellular heterogeneity and rates of symmetric and asymmetric divisions in triple-negative breast cancer. Cell Rep. 24, 3237–3250 (2018).

    CAS  PubMed  Google Scholar 

  185. Ponnurangam, S. et al. Quinomycin A targets Notch signaling pathway in pancreatic cancer stem cells. Oncotarget 7, 3217–3232 (2016).

    PubMed  Google Scholar 

  186. Guerrero-Hernandez, A., Dagnino-Acosta, A. & Verkhratsky, A. An intelligent sarco-endoplasmic reticulum Ca2+ store: release and leak channels have differential access to a concealed Ca2+ pool. Cell Calcium 48, 143–149 (2010).

    CAS  PubMed  Google Scholar 

  187. Roti, G. et al. Complementary genomic screens identify SERCA as a therapeutic target in NOTCH1 mutated cancer. Cancer Cell 23, 390–405 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Roti, G. et al. Leukemia-specific delivery of mutant NOTCH1 targeted therapy. J. Exp. Med. 215, 197–216 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Suisse, A. & Treisman, J. E. Reduced SERCA function preferentially affects Wnt signaling by retaining E-cadherin in the endoplasmic reticulum. Cell Rep. 26, 322–329 e323 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Moloney, D. J. et al. Fringe is a glycosyltransferase that modifies Notch. Nature 406, 369–375 (2000).

    CAS  PubMed  Google Scholar 

  191. Bruckner, K., Perez, L., Clausen, H. & Cohen, S. Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature 406, 411–415 (2000).

    CAS  PubMed  Google Scholar 

  192. Schneider, M. et al. Inhibition of delta-induced notch signaling using fucose analogs. Nat. Chem. Biol. 14, 65–71 (2018).

    CAS  PubMed  Google Scholar 

  193. Takeuchi, H. et al. Two novel protein O-glucosyltransferases that modify sites distinct from POGLUT1 and affect Notch trafficking and signaling. Proc. Natl Acad. Sci. USA 115, E8395–E8402 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Tutar, L., Tutar, E. & Tutar, Y. MicroRNAs and cancer; an overview. Curr. Pharm. Biotechnol. 15, 430–437 (2014).

    CAS  PubMed  Google Scholar 

  195. Chen, J. et al. miR-598 inhibits metastasis in colorectal cancer by suppressing JAG1/Notch2 pathway stimulating EMT. Exp. Cell Res. 352, 104–112 (2017).

    CAS  PubMed  Google Scholar 

  196. Shui, Y. et al. miR-130b-3p inhibits cell invasion and migration by targeting the Notch ligand Delta-like 1 in breast carcinoma. Gene 609, 80–87 (2017).

    CAS  PubMed  Google Scholar 

  197. Jin, Y. et al. Overcoming stemness and chemoresistance in colorectal cancer through miR-195-5p-modulated inhibition of notch signaling. Int. J. Biol. Macromol. 117, 445–453 (2018).

    CAS  PubMed  Google Scholar 

  198. Pan, Y. et al. Lentivirus-mediated overexpression of miR-124 suppresses growth and invasion by targeting JAG1 and EZH2 in gastric cancer. Oncol. Lett. 15, 7450–7458 (2018).

    PubMed  PubMed Central  Google Scholar 

  199. Shin, V. Y. et al. MiR-92 suppresses proliferation and induces apoptosis by targeting EP4/Notch1 axis in gastric cancer. Oncotarget 9, 24209–24220 (2018).

    PubMed  PubMed Central  Google Scholar 

  200. Bettinsoli, P., Ferrari-Toninelli, G., Bonini, S. A., Prandelli, C. & Memo, M. Notch ligand Delta-like 1 as a novel molecular target in childhood neuroblastoma. BMC Cancer 17, 352 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Hanna, J., Hossain, G. S. & Kocerha, J. The potential for microRNA therapeutics and clinical research. Front. Genet. 10, 478 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Salvador-Reyes, L. A. & Luesch, H. Biological targets and mechanisms of action of natural products from marine cyanobacteria. Nat. Prod. Rep. 32, 478–503 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Thomford, N. E. et al. Natural products for drug discovery in the 21st century: innovations for novel drug discovery. Int. J. Mol. Sci. https://doi.org/10.3390/ijms19061578 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  204. Cao, Y. et al. Cinobufagin induces apoptosis of osteosarcoma cells through inactivation of Notch signaling. Eur. J. Pharmacol. 794, 77–84 (2017).

    CAS  PubMed  Google Scholar 

  205. Yu, L. et al. Cisplatin selects for stem-like cells in osteosarcoma by activating Notch signaling. Oncotarget 7, 33055–33068 (2016).

    PubMed  PubMed Central  Google Scholar 

  206. Dai, G. et al. The synergistic antitumor effect of cinobufagin and cisplatin in human osteosarcoma cell line in vitro and in vivo. Oncotarget 8, 85150–85168 (2017).

    PubMed  PubMed Central  Google Scholar 

  207. Kiesel, V. A. & Stan, S. D. Diallyl trisulfide, a chemopreventive agent from Allium vegetables, inhibits alpha-secretases in breast cancer cells. Biochem. Biophys. Res. Commun. 484, 833–838 (2017).

    CAS  PubMed  Google Scholar 

  208. Chen, D. et al. Targeting BMI1+ cancer stem cells overcomes chemoresistance and inhibits metastases in squamous cell carcinoma. Cell Stem Cell 20, 621–634 e626 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Ohtaka, M., Itoh, M. & Tohda, S. BMI1 inhibitors Down-regulate NOTCH signaling and suppress proliferation of acute leukemia cells. Anticancer Res. 37, 6047–6053 (2017).

    CAS  PubMed  Google Scholar 

  210. Arai, M. A. et al. The notch inhibitors isolated from nerium indicum. J. Nat. Prod. 81, 1235–1240 (2018).

    CAS  PubMed  Google Scholar 

  211. Arai, M. A. et al. The Notch inhibitor cowanin accelerates nicastrin degradation. Sci. Rep. 8, 5376 (2018).

    PubMed  PubMed Central  Google Scholar 

  212. Fiorillo, M. et al. Bergamot natural products eradicate cancer stem cells (CSCs) by targeting mevalonate, Rho-GDI-signalling and mitochondrial metabolism. Biochim. Biophys. Acta Bioenerg. 1859, 984–996 (2018).

    CAS  PubMed  Google Scholar 

  213. Su, G., Chen, H. & Sun, X. Baicalein suppresses non small cell lung cancer cell proliferation, invasion and Notch signaling pathway. Cancer Biomark 22, 13–18 (2018).

    CAS  PubMed  Google Scholar 

  214. Zhang, J. et al. Paeoniflorin influences breast cancer cell proliferation and invasion via inhibition of the Notch1 signaling pathway. Mol. Med. Rep. 17, 1321–1325 (2018).

    CAS  PubMed  Google Scholar 

  215. Reiter, R. J. et al. Melatonin, a full service anti-cancer agent: inhibition of initiation, progression and metastasis. Int. J. Mol. Sci. https://doi.org/10.3390/ijms18040843 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Zheng, X. et al. Melatonin inhibits glioblastoma stem-like cells through suppression of EZH2-NOTCH1 signaling axis. Int. J. Biol. Sci. 13, 245–253 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Rajasinghe, L. D., Pindiprolu, R. H. & Gupta, S. V. Delta-tocotrienol inhibits non-small-cell lung cancer cell invasion via the inhibition of NF-kappaB, uPA activator, and MMP-9. OncoTargets Ther. 11, 4301–4314 (2018).

    Google Scholar 

  218. Bommareddy, P. K., Patel, A., Hossain, S. & Kaufman, H. L. Talimogene laherparepvec (T-VEC) and other oncolytic viruses for the treatment of melanoma. Am. J. Clin. Dermatol. 18, 1–15 (2017).

    PubMed  PubMed Central  Google Scholar 

  219. Mato-Berciano, A. et al. A NOTCH-sensitive uPAR-regulated oncolytic adenovirus effectively suppresses pancreatic tumor growth and triggers synergistic anticancer effects with gemcitabine and nab-paclitaxel. Oncotarget 8, 22700–22715 (2017). This study is the first example of Notch-targeted cancer virotherapy.

    PubMed  PubMed Central  Google Scholar 

  220. Keeler, A. M. & Flotte, T. R. Recombinant adeno-associated virus gene therapy in light of luxturna (and Zolgensma and Glybera): where are we, and how did we get here? Annu. Rev. Virol. 6, 601–621 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Xu, K. et al. Lunatic fringe deficiency cooperates with the Met/Caveolin gene amplicon to induce basal-like breast cancer. Cancer Cell 21, 626–641 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Yeh, C. H., Bellon, M. & Nicot, C. FBXW7: a critical tumor suppressor of human cancers. Mol. Cancer 17, 115 (2018).

    PubMed  PubMed Central  Google Scholar 

  223. Sailo, B. L. et al. FBXW7 in cancer: what has been unraveled thus far? Cancers https://doi.org/10.3390/cancers11020246 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Jenkins, R. W. et al. Ex Vivo profiling of PD-1 blockade using organotypic tumor spheroids. Cancer Discov. 8, 196–215 (2018).

    CAS  PubMed  Google Scholar 

  225. Britton, G. J. et al. PKCtheta links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton. eLife https://doi.org/10.7554/eLife.20003 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  226. Kim, J. & Sage, J. Taking SCLC on a bad LSD(1) trip one NOTCH further. Trends Mol. Med. https://doi.org/10.1016/j.molmed.2019.02.009 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  227. Weinmaster, G. & Fischer, J. A. Notch ligand ubiquitylation: what is it good for? Dev. Cell 21, 134–144 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Conner, S. D. Regulation of notch signaling through intracellular transport. Int. Rev. Cell Mol. Biol. 323, 107–127 (2016).

    CAS  PubMed  Google Scholar 

  229. Gordon, W. R. et al. Structural basis for autoinhibition of Notch. Nat. Struct. Mol. Biol. 14, 295–300 (2007).

    CAS  PubMed  Google Scholar 

  230. Groot, A. J. & Vooijs, M. A. The role of Adams in notch signaling. Adv. Exp. Med. Biol. 727, 15–36 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Lu, P. et al. Three-dimensional structure of human γ-secretase. Nature 512, 166 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Steiner, H., Fluhrer, R. & Haass, C. Intramembrane proteolysis by gamma-secretase. J. Biol. Chem. 283, 29627–29631 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Gomez-Lamarca, M. J. et al. Activation of the notch signaling pathway in vivo elicits changes in CSL nuclear dynamics. Dev. Cell 44, 611–623 (2018). This study supports a dynamic model for CSL transcriptional activation by NICD.

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Vilimas, T. et al. Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nat. Med. 13, 70–77 (2007). Vilimas et al. (2007), Vacca et al. (2006), Song et al. (2008), Fernandez-Majada et al. (2007), Hossain et al. (Front. Oncol., 2018) and Hao et al. support the notion of IκB kinases as potentially druggable Notch signalling mediators in different malignancies.

    CAS  PubMed  Google Scholar 

  235. Vacca, A. et al. Notch3 and pre-TCR interaction unveils distinct NF-kappaB pathways in T-cell development and leukemia. EMBO J. 25, 1000–1008 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Song, L. L. et al. Notch-1 associates with IKKalpha and regulates IKK activity in cervical cancer cells. Oncogene 27, 5833–5844 (2008).

    CAS  PubMed  Google Scholar 

  237. Fernandez-Majada, V. et al. Nuclear IKK activity leads to dysregulated Notch-dependent gene expression in colorectal cancer. Proc. Natl Acad. Sci. USA 104, 276–281 (2007).

    CAS  PubMed  Google Scholar 

  238. Hossain, F. et al. Notch signaling regulates mitochondrial metabolism and NF-kappaB activity in triple-negative breast cancer cells via IKKalpha-dependent non-canonical pathways. Front. Oncol. 8, 575 (2018).

    PubMed  PubMed Central  Google Scholar 

  239. Hao, L. et al. Notch-1 activates estrogen receptor-alpha-dependent transcription via IKKalpha in breast cancer cells. Oncogene 29, 201–213 (2010).

    CAS  PubMed  Google Scholar 

  240. Shin, H. M. et al. NOTCH1 can initiate NF-kappaB activation via cytosolic interactions with components of the T cell signalosome. Front. Immunol. 5, 249 (2014).

    PubMed  PubMed Central  Google Scholar 

  241. Sade, H., Krishna, S. & Sarin, A. The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells. J. Biol. Chem 279, 2937–2944 (2004).

    CAS  PubMed  Google Scholar 

  242. Landor, S. K. et al. Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms. Proc. Natl Acad. Sci. USA 108, 18814–18819 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Efferson, C. L. et al. Downregulation of Notch pathway by a gamma-secretase inhibitor attenuates AKT/mammalian target of rapamycin signaling and glucose uptake in an ERBB2 transgenic breast cancer model. Cancer Res. 70, 2476–2484 (2010).

    CAS  PubMed  Google Scholar 

  244. Perumalsamy, L. R., Nagala, M. & Sarin, A. Notch-activated signaling cascade interacts with mitochondrial remodeling proteins to regulate cell survival. Proc. Natl Acad. Sci. USA 107, 6882–6887 (2010). Perumalsamy et al. (2010) and Lee et al. (2013) describe mitochondrial Notch pathways in T cells and glioma stem cells, respectively.

    CAS  PubMed  PubMed Central  Google Scholar 

  245. Lee, K. S. et al. Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway. Genes Dev. 27, 2642–2647 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  246. Xu, J. et al. NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation. J. Clin. Invest. 125, 1579–1590 (2015).

    PubMed  PubMed Central  Google Scholar 

  247. Lee, S. F. et al. Gamma-secretase-regulated proteolysis of the Notch receptor by mitochondrial intermediate peptidase. J. Biol. Chem. 286, 27447–27453 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Pavlov, P. F. et al. Mitochondrial gamma-secretase participates in the metabolism of mitochondria-associated amyloid precursor protein. FASEB J. 25, 78–88 (2011).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors wish to acknowledge the support of the U.S. National Cancer Institute (grant CA-P01-166009) and the Cancer Crusaders Foundation (L.M.).

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  1. These authors contributed equally: Samarpan Majumder, Judy S. Crabtree.

Authors and Affiliations

  1. Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Samarpan Majumder, Judy S. Crabtree & Lucio Miele

  2. Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Samarpan Majumder, Judy S. Crabtree & Lucio Miele

  3. Department of Neuroscience, University of Florida, Gainesville, FL, USA

    Todd E. Golde

  4. McKnight Brain Institute, University of Florida, Gainesville, FL, USA

    Todd E. Golde

  5. Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, USA

    Lisa M. Minter & Barbara A. Osborne

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  1. Samarpan Majumder
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  2. Judy S. Crabtree
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Correspondence to Lucio Miele.

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Glossary

Epithelial–mesenchymal

(EMT). A phenotypic switch, which can be reversible, whereby epithelial cancer cells acquire mesenchymal characteristics, including motility, and potentially stem-like characteristics.

Cancer stem cells

(CSCs). Generally small populations of cells in malignancies that have stem-like characteristics: expression of embryonic or tissue stem cell markers, ability to divide symmetrically or asymmetrically, and resistance to chemotherapy and radiation.

Adenosine

A nucleoside resulting from the enzymatic hydrolysis of extracellular ATP by nucleoside triphosphate diphosphohydrolase 1 (also known as CD39), nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) and ecto-5′ nucleotidase (also known as CD73).

Myeloid-derived suppressor cells

(MDSCs). These include two main subtypes of immature myeloid cells (polymorphonuclear MDSCs and monocytic MDSCs), which are released from the bone marrow and migrate to the tumour microenvironment, where they suppress tumour immunity through a variety of mechanisms.

Chimeric antigen receptor

(CAR). A recombinant transmembrane receptor designed to bind specific antigens and activate transduced patient T cells.

BiTE

(Bispecific T cell engager). A recombinant bispecific antibody that uses one antigen-binding site to engage a tumour-selective antigen and an anti-CD3 antigen-binding site to non-specifically activate the T cell receptor of tumour-infiltrating lymphocytes.

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Majumder, S., Crabtree, J.S., Golde, T.E. et al. Targeting Notch in oncology: the path forward. Nat Rev Drug Discov 20, 125–144 (2021). https://doi.org/10.1038/s41573-020-00091-3

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