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Towards targeting of shared mechanisms of cancer metastasis and therapy resistance

Abstract

Resistance to therapeutic treatment and metastatic progression jointly determine a fatal outcome of cancer. Cancer metastasis and therapeutic resistance are traditionally studied as separate fields using non-overlapping strategies. However, emerging evidence, including from in vivo imaging and in vitro organotypic culture, now suggests that both programmes cooperate and reinforce each other in the invasion niche and persist upon metastatic evasion. As a consequence, cancer cell subpopulations exhibiting metastatic invasion undergo multistep reprogramming that — beyond migration signalling — supports repair programmes, anti-apoptosis processes, metabolic adaptation, stemness and survival. Shared metastasis and therapy resistance signalling are mediated by multiple mechanisms, such as engagement of integrins and other context receptors, cell–cell communication, stress responses and metabolic reprogramming, which cooperate with effects elicited by autocrine and paracrine chemokine and growth factor cues present in the activated tumour microenvironment. These signals empower metastatic cells to cope with therapeutic assault and survive. Identifying nodes shared in metastasis and therapy resistance signalling networks should offer new opportunities to improve anticancer therapy beyond current strategies, to eliminate both nodular lesions and cells in metastatic transit.

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Fig. 1: Invasion-associated reprogramming.
Fig. 2: Invasion-associated reprogramming from the extracellular matrix.
Fig. 3: Mechanisms of repair and cell survival.
Fig. 4: Cooperation and redundancy of survival signalling in single-cell and collective invasion during metastasis.
Fig. 5: Targeting metastasis-associated therapy resistance programmes.

References

  1. Welch, D. R. & Hurst, D. R. Defining the hallmarks of metastasis. Cancer Res. 79, 3011–3027 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Friedl, P. & Alexander, S. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147, 992–1009 (2011).

    CAS  PubMed  Google Scholar 

  3. Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Obenauf, A. C. et al. Therapy-induced tumour secretomes promote resistance and tumour progression. Nature 520, 368–372 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Meredith, J. E., Fazeli, B. & Schwartz, M. A. The extracellular matrix as a cell survival factor. Mol. Biol. Cell 4, 953–961 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Alexander, S. & Friedl, P. Cancer invasion and resistance: interconnected processes of disease progression and therapy failure. Trends Mol. Med. 18, 13–26 (2012).

    PubMed  Google Scholar 

  7. Casasent, A. K. et al. Multiclonal invasion in breast tumors identified by topographic single cell sequencing. Cell 172, 205–217.e12 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kim, C. et al. Chemoresistance evolution in triple-negative breast cancer delineated by single-cell sequencing. Cell 173, 879–893.e13 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Yilmaz, M. & Christofori, G. Mechanisms of motility in metastasizing cells. Mol. Cancer Res. 8, 629–642 (2010).

    CAS  PubMed  Google Scholar 

  10. Chaffer, C. L., Juan, B. P. S., Lim, E. & Weinberg, R. A. EMT, cell plasticity and metastasis. Cancer Metast Rev. 35, 645–654 (2016).

    Google Scholar 

  11. Haeger, A. et al. Collective cancer invasion forms an integrin-dependent radioresistant niche. J. Exp. Med. 217, e20181184 (2020).

    PubMed  Google Scholar 

  12. Padmanaban, V. et al. E-cadherin is required for metastasis in multiple models of breast cancer. Nature 573, 439–444 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Odenthal, J., Takes, R. & Friedl, P. Plasticity of tumor cell invasion: governance by growth factors and cytokines. Carcinogenesis 37, 1117–1128 (2016).

    CAS  PubMed  Google Scholar 

  14. Moose, D. L. et al. Cancer cells resist mechanical destruction in circulation via RhoA/actomyosin-dependent mechano-adaptation. Cell Rep. 30, 3864–3874.e6 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Kosmalska, A. J. et al. Physical principles of membrane remodelling during cell mechanoadaptation. Nat. Commun. 6, 7292 (2015).

    CAS  PubMed  Google Scholar 

  16. Zanotelli, M. R. et al. Energetic costs regulated by cell mechanics and confinement are predictive of migration path during decision-making. Nat. Commun. 10, 4185 (2019).

    PubMed  PubMed Central  Google Scholar 

  17. Wolf, K. et al. Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force. J. Cell Biol. 201, 1069–1084 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. te Boekhorst, V. et al. Calpain-2 regulates hypoxia/HIF-induced amoeboid reprogramming and metastasis. Curr. Biol. https://doi.org/10.1016/j.cub.2021.11.040 (2021).

    Article  Google Scholar 

  19. Friedl, P. & Gilmour, D. Collective cell migration in morphogenesis, regeneration and cancer. Nat. Rev. Mol. Cell Biol. 10, 445–457 (2009).

    CAS  PubMed  Google Scholar 

  20. Khalil, A. A. et al. Collective invasion induced by an autocrine purinergic loop through connexin-43 hemichannels. J. Cell Biol. 219, e201911120 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Reffay, M. et al. Interplay of RhoA and mechanical forces in collective cell migration driven by leader cells. Nat. Cell Biol. 16, 217–223 (2014).

    CAS  PubMed  Google Scholar 

  22. Aceto, N. et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158, 1110–1122 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Ilina, O. et al. Cell–cell adhesion and 3D matrix confinement determine jamming transitions in breast cancer invasion. Nat. Cell Biol. 22, 1103–1115 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Hidalgo-Carcedo, C. et al. Collective cell migration requires suppression of actomyosin at cell–cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6. Nat. Cell Biol. 13, 49–59 (2011).

    CAS  PubMed  Google Scholar 

  25. Plutoni, C. et al. P-cadherin promotes collective cell migration via a Cdc42-mediated increase in mechanical forces. J. Cell Biol. 212, 199–217 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Gumbiner, B. M. & Kim, N.-G. The Hippo-YAP signaling pathway and contact inhibition of growth. J. Cell Sci. 127, 709–717 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Bernat-Peguera, A. et al. PDGFR-induced autocrine SDF-1 signaling in cancer cells promotes metastasis in advanced skin carcinoma. Oncogene 38, 5021–5037 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Wrenn, E. D. et al. Regulation of collective metastasis by nanolumenal signaling. Cell 183, 395–410.e19 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Roussos, E. T., Condeelis, J. S. & Patsialou, A. Chemotaxis in cancer. Nat. Rev. Cancer 11, 573–587 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Schneider, G., Sellers, Z. P., Abdel-Latif, A., Morris, A. J. & Ratajczak, M. Z. Bioactive lipids, LPC and LPA, are novel prometastatic factors and their tissue levels increase in response to radio/chemotherapy. Mol. Cancer Res. 12, 1560–1573 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Shi, Y., Riese, D. J. & Shen, J. The role of the CXCL12/CXCR4/CXCR7 chemokine axis in cancer. Front. Pharmacol. 11, 574667 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Lemmon, M. A. & Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 141, 1117–1134 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Zweemer, A. J. M. et al. Apoptotic bodies elicit Gas6-mediated migration of AXL-expressing tumor cells. Mol. Cancer Res. 15, 1656–1666 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Weigelin, B., Bakker, G.-J. & Friedl, P. Intravital third harmonic generation microscopy of collective melanoma cell invasion. IntraVital 1, 32–43 (2012).

    PubMed  Google Scholar 

  35. Cooper, J. & Giancotti, F. G. Integrin signaling in cancer: mechanotransduction, stemness, epithelial plasticity, and therapeutic resistance. Cancer Cell 35, 347–367 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Hamidi, H. & Ivaska, J. Every step of the way: integrins in cancer progression and metastasis. Nat. Rev. Cancer 18, 533–548 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Yang, H. W. et al. Cooperative activation of PI3K by Ras and Rho family small GTPases. Mol. Cell 47, 281–290 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Rubashkin, M. G. et al. Force engages vinculin and promotes tumor progression by enhancing PI3K activation of phosphatidylinositol (3,4,5)-triphosphate. Cancer Res. 74, 4597–4611 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Miroshnikova, Y. A. et al. α5β1-Integrin promotes tension-dependent mammary epithelial cell invasion by engaging the fibronectin synergy site. Mol. Biol. Cell 28, 2958–2977 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Totaro, A., Panciera, T. & Piccolo, S. YAP/TAZ upstream signals and downstream responses. Nat. Cell Biol. 20, 888–899 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Benham-Pyle, B. W., Pruitt, B. L. & Nelson, W. J. Mechanical strain induces E-cadherin–dependent Yap1 and β-catenin activation to drive cell cycle entry. Science 348, 1024–1027 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Piccolo, S., Dupont, S. & Cordenonsi, M. The biology of YAP/TAZ: Hippo signaling and beyond. Physiol. Rev. 94, 1287–1312 (2014).

    CAS  PubMed  Google Scholar 

  43. Zanconato, F., Cordenonsi, M. & Piccolo, S. YAP and TAZ: a signalling hub of the tumour microenvironment. Nat. Rev. Cancer 19, 454–464 (2019).

    CAS  PubMed  Google Scholar 

  44. Denais, C. M. et al. Nuclear envelope rupture and repair during cancer cell migration. Science 352, 353–358 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Vietri, M., Radulovic, M. & Stenmark, H. The many functions of ESCRTs. Nat. Rev. Mol. Cell Bio 21, 25–42 (2020).

    CAS  Google Scholar 

  46. Raab, M. et al. ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death. Science 352, 359–362 (2016).

    CAS  PubMed  Google Scholar 

  47. Gensbittel, V. et al. Mechanical adaptability of tumor cells in metastasis. Dev. Cell 56, 164–179 (2021).

    CAS  PubMed  Google Scholar 

  48. Roos, W. P., Thomas, A. D. & Kaina, B. DNA damage and the balance between survival and death in cancer biology. Nat. Rev. Cancer 16, 20–33 (2016).

    CAS  PubMed  Google Scholar 

  49. Blackford, A. N. & Jackson, S. P. ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol. Cell 66, 801–817 (2017).

    CAS  PubMed  Google Scholar 

  50. Hou, H., Sun, D. & Zhang, X. The role of MDM2 amplification and overexpression in therapeutic resistance of malignant tumors. Cancer Cell Int. 19, 216 (2019).

    PubMed  PubMed Central  Google Scholar 

  51. Schmidt, A.-K. et al. The p53/p73 - p21CIP1 tumor suppressor axis guards against chromosomal instability by restraining CDK1 in human cancer cells. Oncogene 40, 1–16 (2020).

    Google Scholar 

  52. Collins, A. R., Ai-guo, M. & Duthie, S. J. The kinetics of repair of oxidative DNA damage (strand breaks and oxidised pyrimidines) in human cells. Mutat. Res. Dna Repair. 336, 69–77 (1995).

    CAS  PubMed  Google Scholar 

  53. Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Saleh, T., Tyutyunyk-Massey, L. & Gewirtz, D. A. Tumor cell escape from therapy-induced senescence as a model of disease recurrence after dormancy. Cancer Res. 79, 1044–1046 (2019).

    CAS  PubMed  Google Scholar 

  55. Fernandez-Capetillo, O. et al. DNA damage-induced G2–M checkpoint activation by histone H2AX and 53BP1. Nat. Cell Biol. 4, 993–997 (2002).

    CAS  PubMed  Google Scholar 

  56. Daley, J. M. & Sung, P. 53BP1, BRCA1, and the choice between recombination and end joining at DNA double-strand breaks. Mol. Cell Biol. 34, 1380–1388 (2014).

    PubMed  PubMed Central  Google Scholar 

  57. Hofmann, T. G. et al. Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. Nat. Cell Biol. 4, 1–10 (2002).

    CAS  PubMed  Google Scholar 

  58. Aubrey, B. J., Kelly, G. L., Janic, A., Herold, M. J. & Strasser, A. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ. 25, 104–113 (2018).

    CAS  PubMed  Google Scholar 

  59. Shamas-Din, A., Brahmbhatt, H., Leber, B. & Andrews, D. W. BH3-only proteins: orchestrators of apoptosis. Biochim. Biophys. Acta 1813, 508–520 (2011).

    CAS  PubMed  Google Scholar 

  60. Surova, O. & Zhivotovsky, B. Various modes of cell death induced by DNA damage. Oncogene 32, 3789–3797 (2013).

    CAS  PubMed  Google Scholar 

  61. Hamdi, M. et al. DNA damage in transcribed genes induces apoptosis via the JNK pathway and the JNK-phosphatase MKP-1. Oncogene 24, 7135–7144 (2005).

    CAS  PubMed  Google Scholar 

  62. Brozovic, A. et al. Long-term activation of SAPK/JNK, p38 kinase and fas-L expression by cisplatin is attenuated in human carcinoma cells that acquired drug resistance. Int. J. Cancer 112, 974–985 (2004).

    CAS  PubMed  Google Scholar 

  63. Rödel, F. et al. Survivin as a radioresistance factor, and prognostic and therapeutic target for radiotherapy in rectal cancer. Cancer Res. 65, 4881–4887 (2005).

    PubMed  Google Scholar 

  64. Sanchez-Vega, F. et al. Oncogenic signaling pathways in the cancer genome atlas. Cell 173, 321–337.e10 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Housman, G. et al. Drug resistance in cancer: an overview. Cancers 6, 1769–1792 (2014).

    PubMed  PubMed Central  Google Scholar 

  66. Gupta, S. K., Singh, P., Ali, V. & Verma, M. Role of membrane-embedded drug efflux ABC transporters in the cancer chemotherapy. Oncol. Rev. 14, 448 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Siemens, D. R. et al. Hypoxia increases tumor cell shedding of MHC class I chain-related molecule: role of nitric oxide. Cancer Res. 68, 4746–4753 (2008).

    CAS  PubMed  Google Scholar 

  69. Yang, W., Li, Y., Gao, R., Xiu, Z. & Sun, T. MHC class I dysfunction of glioma stem cells escapes from CTL-mediated immune response via activation of Wnt/β-catenin signaling pathway. Oncogene 39, 1098–1111 (2020).

    CAS  PubMed  Google Scholar 

  70. Strand, S. et al. Cleavage of CD95 by matrix metalloproteinase-7 induces apoptosis resistance in tumour cells. Oncogene 23, 3732–3736 (2004).

    CAS  PubMed  Google Scholar 

  71. Jiao, S. et al. Differences in tumor microenvironment dictate t helper lineage polarization and response to immune checkpoint therapy. Cell 179, 1177–1190.e13 (2019).

    CAS  PubMed  Google Scholar 

  72. Suarez-Carmona, M., Lesage, J., Cataldo, D. & Gilles, C. EMT and inflammation: inseparable actors of cancer progression. Mol. Oncol. 11, 805–823 (2017).

    PubMed  PubMed Central  Google Scholar 

  73. Li, Y., Patel, S. P., Roszik, J. & Qin, Y. Hypoxia-driven immunosuppressive metabolites in the tumor microenvironment: new approaches for combinational immunotherapy. Front. Immunol. 9, 1591 (2018).

    PubMed  PubMed Central  Google Scholar 

  74. Logue, J. S. & Morrison, D. K. Complexity in the signaling network: insights from the use of targeted inhibitors in cancer therapy. Gene Dev. 26, 641–650 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Rothenberger, N., Somasundaram, A. & Stabile, L. P. The role of the estrogen pathway in the tumor microenvironment. Int. J. Mol. Sci. 19, 611 (2018).

    PubMed Central  Google Scholar 

  76. Chen, S. & Sang, N. Hypoxia-inducible factor-1: a critical player in the survival strategy of stressed cells. J. Cell Biochem. 117, 267–278 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Rankin, E. B. & Giaccia, A. J. Hypoxic control of metastasis. Science 352, 175–180 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Dasgupta, I. & McCollum, D. Control of cellular responses to mechanical cues through YAP/TAZ regulation. J. Biol. Chem. 294, 17693–17706 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Muñoz-Gámez, J. A. et al. PARP-1 is involved in autophagy induced by DNA damage. Autophagy 5, 61–74 (2009).

    PubMed  Google Scholar 

  80. Stambolic, V. et al. Regulation of PTEN transcription by p53. Mol. Cell 8, 317–325 (2001).

    CAS  PubMed  Google Scholar 

  81. Cao, C. et al. Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res. 66, 10040–10047 (2006).

    CAS  PubMed  Google Scholar 

  82. Lin, R.-K. & Wang, Y.-C. Dysregulated transcriptional and post-translational control of DNA methyltransferases in cancer. Cell Biosci. 4, 46 (2014).

    PubMed  PubMed Central  Google Scholar 

  83. Poole, C. J. & Riggelen, J. V. MYC — master regulator of the cancer epigenome and transcriptome. Genes-basel 8, 142 (2017).

    PubMed Central  Google Scholar 

  84. Cui, H. et al. DNA methyltransferase 3A isoform b contributes to repressing E-cadherin through cooperation of DNA methylation and H3K27/H3K9 methylation in EMT-related metastasis of gastric cancer. Oncogene 37, 4358–4371 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Liu, H. et al. Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis. Cell Death Differ. 27, 966–983 (2020).

    CAS  PubMed  Google Scholar 

  86. Jung, K. H. et al. HDAC2 overexpression confers oncogenic potential to human lung cancer cells by deregulating expression of apoptosis and cell cycle proteins. J. Cell Biochem. 113, 2167–2177 (2012).

    CAS  PubMed  Google Scholar 

  87. Cerbo, V. D. & Schneider, R. Cancers with wrong HATs: the impact of acetylation. Brief. Funct. Genomics 12, 231–243 (2013).

    PubMed  Google Scholar 

  88. Chen, Y. et al. The role of histone methylation in the development of digestive cancers: a potential direction for cancer management. Signal. Transduct. Target. Ther. 5, 143 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Kim, K. H. & Roberts, C. W. M. Targeting EZH2 in cancer. Nat. Med. 22, 128–134 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Cheng, Y. et al. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal. Transduct. Target. Ther. 4, 62 (2019).

    PubMed  PubMed Central  Google Scholar 

  91. Lehmann, S. et al. Hypoxia induces a HIF-1-dependent transition from collective-to-amoeboid dissemination in epithelial cancer cells. Curr. Biol. 27, 392–400 (2017).

    CAS  PubMed  Google Scholar 

  92. Yang, H. et al. Overexpression of histone deacetylases in cancer cells is controlled by interplay of transcription factors and epigenetic modulators. FASEB J. 28, 4265–4279 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Tang, Z. et al. HDAC1 triggers the proliferation and migration of breast cancer cells via upregulation of interleukin-8. Biol. Chem. 398, 1347–1356 (2017).

    CAS  PubMed  Google Scholar 

  94. Matus, D. Q. et al. Invasive cell fate requires G1 cell-cycle arrest and histone deacetylase-mediated changes in gene expression. Dev. Cell 35, 162–174 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Li, S. et al. Histone deacetylase 1 promotes glioblastoma cell proliferation and invasion via activation of PI3K/AKT and MEK/ERK signaling pathways. Brain Res. 1692, 154–162 (2018).

    CAS  PubMed  Google Scholar 

  96. An, P. et al. HDAC8 promotes the dissemination of breast cancer cells via AKT/GSK-3β/Snail signals. Oncogene 39, 4956–4969 (2020).

    CAS  PubMed  Google Scholar 

  97. Marks, P. A. et al. Histone deacetylases and cancer: causes and therapies. Nat. Rev. Cancer 1, 194–202 (2001).

    CAS  PubMed  Google Scholar 

  98. Tran, A. D.-A. et al. HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions. J. Cell Sci. 120, 1469–1479 (2007).

    CAS  PubMed  Google Scholar 

  99. Moore, G. Y. & Pidgeon, G. P. Cross-talk between cancer cells and the tumour microenvironment: the role of the 5-lipoxygenase pathway. Int. J. Mol. Sci. 18, 236 (2017).

    PubMed Central  Google Scholar 

  100. Lee, K. J. et al. EGFR signaling promotes resistance to CHK1 inhibitor prexasertib in triple negative breast cancer. Cancer Drug Resist. 3, 980–991 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Wang, S. J. et al. Efficient blockade of locally reciprocated tumor-macrophage signaling using a TAM-avid nanotherapy. Sci. Adv. 6, eaaz8521 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Jiang, M., Gu, D., Dai, J., Huang, Q. & Tian, L. Dark side of cytotoxic therapy: chemoradiation-induced cell death and tumor repopulation. Trends Cancer 6, 419–431 (2020).

    CAS  PubMed  Google Scholar 

  103. Tape, C. J. et al. Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation. Cell 165, 910–920 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Orgaz, J. L. et al. Myosin II reactivation and cytoskeletal remodeling as a hallmark and a vulnerability in melanoma therapy resistance. Cancer Cell 37, 85–103.e9 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Petitclerc, E. et al. Integrin alpha(v)beta3 promotes M21 melanoma growth in human skin by regulating tumor cell survival. Cancer Res. 59, 2724–2730 (1999).

    CAS  PubMed  Google Scholar 

  106. Jenndahl, L. E., Taylor-Papadimitriou, J. & Baeckström, D. Characterization of integrin and anchorage dependence in mammary epithelial cells following c-erbB2-induced epithelial-mesenchymal transition. Tumor Biol. 27, 50–58 (2005).

    Google Scholar 

  107. Eke, I. et al. β1 integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy. J. Clin. Invest. 122, 1529–1540 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Jung, S. H. et al. Integrin α6β4-Src-AKT signaling induces cellular senescence by counteracting apoptosis in irradiated tumor cells and tissues. Cell Death Differ. 26, 245–259 (2019).

    CAS  PubMed  Google Scholar 

  109. Walker, J. L. & Assoian, R. K. Integrin-dependent signal transduction regulating cyclin D1 expression and G1 phase cell cycle progression. Cancer Metast Rev. 24, 383–393 (2005).

    CAS  Google Scholar 

  110. Ghebeh, H. et al. Fascin is involved in the chemotherapeutic resistance of breast cancer cells predominantly via the PI3K/Akt pathway. Br. J. Cancer 111, 1552–1561 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Kleinschmidt, E. G. & Schlaepfer, D. D. Focal adhesion kinase signaling in unexpected places. Curr. Opin. Cell Biol. 45, 24–30 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Hermann, M.-R. et al. Integrins synergise to induce expression of the MRTF-A–SRF target gene ISG15 for promoting cancer cell invasion. J. Cell Sci. 129, 1391–1403 (2016).

    CAS  PubMed  Google Scholar 

  113. Yu, O. M. et al. YAP and MRTF-A, transcriptional co-activators of RhoA-mediated gene expression, are critical for glioblastoma tumorigenicity. Oncogene 37, 5492–5507 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Baltes, F. et al. β1-Integrin binding to collagen type 1 transmits breast cancer cells into chemoresistance by activating ABC efflux transporters. Biochim. Biophys. 1867, 118663 (2020).

    CAS  Google Scholar 

  115. Ravindranath, A. K. et al. CD44 promotes multi-drug resistance by protecting P-glycoprotein from FBXO21-mediated ubiquitination. Oncotarget 6, 26308–26321 (2015).

    PubMed  PubMed Central  Google Scholar 

  116. Lv, L. et al. Upregulation of CD44v6 contributes to acquired chemoresistance via the modulation of autophagy in colon cancer SW480 cells. Tumor Biol. 37, 8811–8824 (2016).

    CAS  Google Scholar 

  117. Das, S. et al. Discoidin domain receptor 1 receptor tyrosine kinase induces cyclooxygenase-2 and promotes chemoresistance through nuclear factor-κB pathway activation. Cancer Res. 66, 8123–8130 (2006).

    CAS  PubMed  Google Scholar 

  118. Bierbaumer, L. et al. YAP/TAZ inhibition reduces metastatic potential of Ewing sarcoma cells. Oncogenesis 10, 2 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Shao, D. D. et al. KRAS and YAP1 converge to regulate EMT and tumor survival. Cell 158, 171–184 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Kapoor, A. et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell 158, 185–197 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Stowers, R. S. et al. Matrix stiffness induces a tumorigenic phenotype in mammary epithelium through changes in chromatin accessibility. Nat. Biomed. Eng. 3, 1009–1019 (2019).

    PubMed  PubMed Central  Google Scholar 

  122. Jain, N., Iyer, K. V., Kumar, A. & Shivashankar, G. V. Cell geometric constraints induce modular gene-expression patterns via redistribution of HDAC3 regulated by actomyosin contractility. Proc. Natl Acad. Sci. USA 110, 11349–11354 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Sharda, A. et al. Elevated HDAC activity and altered histone phospho-acetylation confer acquired radio-resistant phenotype to breast cancer cells. Clin. Epigenetics 12, 4 (2020).

    PubMed  PubMed Central  Google Scholar 

  124. Conway, J. R. W. et al. Intravital imaging to monitor therapeutic response in moving hypoxic regions resistant to PI3K pathway targeting in pancreatic cancer. Cell Rep. 23, 3312–3326 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Martin, S. et al. An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAFV600E inhibitor-resistant metastatic melanoma cells. Autophagy 13, 1512–1527 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Klapproth, E. et al. Whole exome sequencing identifies mTOR and KEAP1 as potential targets for radiosensitization of HNSCC cells refractory to EGFR and β1 integrin inhibition. Oncotarget 9, 18099–18114 (2018).

    PubMed  PubMed Central  Google Scholar 

  127. Ichimura, Y. et al. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol. Cell 51, 618–631 (2013).

    CAS  PubMed  Google Scholar 

  128. Meir, Z., Mukamel, Z., Chomsky, E., Lifshitz, A. & Tanay, A. Single-cell analysis of clonal maintenance of transcriptional and epigenetic states in cancer cells. Nat. Genet. 52, 709–718 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Oehme, I. et al. Histone deacetylase 10 promotes autophagy-mediated cell survival. Proc. Natl Acad. Sci. USA 110, E2592–E2601 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Kenific, C. M., Wittmann, T. & Debnath, J. Autophagy in adhesion and migration. J. Cell Sci. 129, 3685–3693 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Zhao, B. et al. Exploiting temporal collateral sensitivity in tumor clonal evolution. Cell 165, 234–246 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Sharifi, M. N. et al. Autophagy promotes focal adhesion disassembly and cell motility of metastatic tumor cells through the direct interaction of paxillin with LC3. Cell Rep. 15, 1660–1672 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Meyer, A. S., Zweemer, A. J. M. & Lauffenburger, D. A. The AXL receptor is a sensor of ligand spatial heterogeneity. Cell Syst. 1, 25–36 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Miller, M. A. et al. Reduced proteolytic shedding of receptor tyrosine kinases is a post-translational mechanism of kinase inhibitor resistance. Cancer Discov. 6, 382–399 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Romero-Garcia, S., Prado-Garcia, H. & Carlos-Reyes, A. Role of DNA methylation in the resistance to therapy in solid tumors. Front. Oncol. 10, 1152 (2020).

    PubMed  PubMed Central  Google Scholar 

  136. Su, C.-W. et al. Loss of TIMP3 by promoter methylation of Sp1 binding site promotes oral cancer metastasis. Cell Death Dis. 10, 793 (2019).

    PubMed  PubMed Central  Google Scholar 

  137. Gartung, A. et al. Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor. Proc. Natl Acad. Sci. USA 116, 201803999 (2019).

    Google Scholar 

  138. Thomas, A. et al. Tumor mutational burden is a determinant of immune-mediated survival in breast cancer. Oncoimmunology 7, 1–12 (2018).

    CAS  Google Scholar 

  139. Hughes, R. et al. Perivascular M2 macrophages stimulate tumor relapse after chemotherapy. Cancer Res. 75, 3479–3491 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Divine, L. M. et al. AXL modulates extracellular matrix protein expression and is essential for invasion and metastasis in endometrial cancer. Oncotarget 5, 77291–77305 (2014).

    Google Scholar 

  141. Karagiannis, G. S. et al. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Sci. Transl. Med. 9, eaan0026 (2017).

    PubMed  PubMed Central  Google Scholar 

  142. Haque, A. S. M. R. et al. CD206+ tumor-associated macrophages promote proliferation and invasion in oral squamous cell carcinoma via EGF production. Sci. Rep. 9, 14611 (2019).

    PubMed  PubMed Central  Google Scholar 

  143. Blockhuys, S. et al. X-radiation enhances the collagen type I strap formation and migration potentials of colon cancer cells. Oncotarget 7, 71390–71399 (2016).

    PubMed  PubMed Central  Google Scholar 

  144. Wang, T. et al. High expression of intratumoral stromal proteins is associated with chemotherapy resistance in breast cancer. Oncotarget 7, 55155–55168 (2015).

    Google Scholar 

  145. Rong, G., Kang, H., Wang, Y., Hai, T. & Sun, H. Candidate markers that associate with chemotherapy resistance in breast cancer through the study on taxotere-induced damage to tumor microenvironment and gene expression profiling of carcinoma-associated fibroblasts (CAFs). PLoS ONE 8, e70960 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Zhang, X., Tang, N., Hadden, T. J. & Rishi, A. K. Akt, FoxO and regulation of apoptosis. Biochim. Biophys. Acta 1813, 1978–1986 (2011).

    CAS  PubMed  Google Scholar 

  147. Mitsiades, C. S. et al. Activation of NF-κB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. Oncogene 21, 5673–5683 (2002).

    CAS  PubMed  Google Scholar 

  148. Verzella, D. et al. Life, death, and autophagy in cancer: NF-κB turns up everywhere. Cell Death Dis. 11, 210 (2020).

    PubMed  PubMed Central  Google Scholar 

  149. Rubinsztein, D. C., Codogno, P. & Levine, B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat. Rev. Drug Discov. 11, 709–730 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Braicu et al. A comprehensive review on MAPK: a promising therapeutic target in cancer. Cancers 11, 1618 (2019).

    CAS  PubMed Central  Google Scholar 

  151. Joyce, D. et al. Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-κB-dependent pathway. J. Biol. Chem. 274, 25245–25249 (1999).

    CAS  PubMed  Google Scholar 

  152. Veevers-Lowe, J., Ball, S. G., Shuttleworth, A. & Kielty, C. M. Mesenchymal stem cell migration is regulated by fibronectin through α5β1-integrin-mediated activation of PDGFR-β and potentiation of growth factor signals. J. Cell Sci. 124, 1288–1300 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Schwartz, M. A. & Ginsberg, M. H. Networks and crosstalk: integrin signalling spreads. Nat. Cell Biol. 4, E65–E68 (2002).

    CAS  PubMed  Google Scholar 

  154. Guo, W. et al. β4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell 126, 489–502 (2006).

    CAS  PubMed  Google Scholar 

  155. Javadi, S., Zhiani, M., Mousavi, M. A. & Fathi, M. Crosstalk between epidermal growth factor receptors (EGFR) and integrins in resistance to EGFR tyrosine kinase inhibitors (TKIs) in solid tumors. Eur. J. Cell Biol. 99, 151083 (2020).

    CAS  PubMed  Google Scholar 

  156. Mui, K. L., Chen, C. S. & Assoian, R. K. The mechanical regulation of integrin–cadherin crosstalk organizes cells, signaling and forces. J. Cell Sci. 129, 1093–1100 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Gravdal, K., Halvorsen, O. J., Haukaas, S. A. & Akslen, L. A. A Switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin. Cancer Res. 13, 7003–7011 (2007).

    CAS  PubMed  Google Scholar 

  158. Canel, M., Serrels, A., Frame, M. C. & Brunton, V. G. E-cadherin-integrin crosstalk in cancer invasion and metastasis. J. Cell Sci. 126, 393–401 (2013).

    CAS  PubMed  Google Scholar 

  159. Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Bronsert, P. et al. Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer–host interface. J. Pathol. 234, 410–422 (2014).

    CAS  PubMed  Google Scholar 

  161. Bedzhov, I. & Zernicka-Goetz, M. Cell death and morphogenesis during early mouse development: are they interconnected? Bioessays 37, 372–378 (2015).

    PubMed  PubMed Central  Google Scholar 

  162. Riley, J. K., Carayannopoulos, M. O., Wyman, A. H., Chi, M. & Moley, K. H. Phosphatidylinositol 3-kinase activity is critical for glucose metabolism and embryo survival in murine blastocysts. J. Biol. Chem. 281, 6010–6019 (2006).

    CAS  PubMed  Google Scholar 

  163. Liu, L., Wang, Y. & YU, Q. The PI3K/Akt signaling pathway exerts effects on the implantation of mouse embryos by regulating the expression of RhoA. Int. J. Mol. Med. 33, 1089–1096 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Xue, G. & Hemmings, B. A. PKB/Akt–dependent regulation of cell motility. J. Natl Cancer Inst. 105, 393–404 (2013).

    CAS  PubMed  Google Scholar 

  165. Friedl, P. & Mayor, R. Tuning collective cell migration by cell–cell junction regulation. Cold Spring Harb. Perspect. Biol. 9, a029199 (2017).

    PubMed  PubMed Central  Google Scholar 

  166. Chabner, B. A. Does chemotherapy induce metastases? Oncol 23, 273–274 (2018).

    Google Scholar 

  167. Morris, T. et al. Effects of low-dose aspirin on acute inflammatory responses in humans. J. Immunol. 183, 2089–2096 (2009).

    CAS  PubMed  Google Scholar 

  168. Rothwell, P. M. et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 379, 1591–1601 (2012).

    CAS  PubMed  Google Scholar 

  169. Perelmuter, V. M. et al. Mechanisms behind prometastatic changes induced by neoadjuvant chemotherapy in the breast cancer microenvironment. Breast Cancer Targets Ther. 11, 209–219 (2019).

    CAS  Google Scholar 

  170. Symmans, W. F. et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J. Clin. Oncol. 25, 4414–4422 (2007).

    PubMed  Google Scholar 

  171. Khalil, A. A. et al. Collective invasion in ductal and lobular breast cancer associates with distant metastasis. Clin. Exp. Metastas 34, 421–429 (2017).

    Google Scholar 

  172. Olmos, D. et al. Circulating tumour cell (CTC) counts as intermediate end points in castration-resistant prostate cancer (CRPC): a single-centre experience. Ann. Oncol. 20, 27–33 (2009).

    CAS  PubMed  Google Scholar 

  173. Koonce, N. A. et al. Real-time monitoring of circulating tumor cell (CTC) release after nanodrug or tumor radiotherapy using in vivo flow cytometry. Biochem. Biophys. Res. Commun. 492, 507–512 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Lorente, D. et al. Decline in circulating tumor cell count and treatment outcome in advanced prostate cancer. Eur. Urol. 70, 985–992 (2016).

    PubMed  PubMed Central  Google Scholar 

  175. Misek, S. A. et al. Rho-mediated signaling promotes BRAF inhibitor resistance in de-differentiated melanoma cells. Oncogene 39, 1466–1483 (2020).

    CAS  PubMed  Google Scholar 

  176. Hirata, E. et al. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling. Cancer Cell 27, 574–588 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Eke, I., Storch, K., Krause, M. & Cordes, N. Cetuximab attenuates its cytotoxic and radiosensitizing potential by inducing fibronectin biosynthesis. Cancer Res. 73, 5869–5879 (2013).

    CAS  PubMed  Google Scholar 

  178. Yamauchi, M. et al. N-cadherin expression is a potential survival mechanism of gefitinib-resistant lung cancer cells. Am. J. Cancer Res. 1, 823–833 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Li, Y. & Seto, E. HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb. Perspect. Med. 6, a026831 (2016).

    PubMed  PubMed Central  Google Scholar 

  180. Bian, X., Liang, Z., Feng, A., Salgado, E. & Shim, H. HDAC inhibitor suppresses proliferation and invasion of breast cancer cells through regulation of miR-200c targeting CRKL. Biochem. Pharmacol. 147, 30–37 (2018).

    CAS  PubMed  Google Scholar 

  181. Bruchard, M. et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat. Med. 19, 57–64 (2013).

    CAS  PubMed  Google Scholar 

  182. Yuan, H. et al. SETD2 restricts prostate cancer metastasis by integrating EZH2 and AMPK signaling pathways. Cancer Cell 38, 350–365.e7 (2020).

    CAS  PubMed  Google Scholar 

  183. Zhang, H.-H. & Guo, X.-L. Combinational strategies of metformin and chemotherapy in cancers. Cancer Chemoth Pharm. 78, 13–26 (2016).

    CAS  Google Scholar 

  184. Tirosh, I. et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189–196 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Stopfer, L. E., Mesfin, J. M., Joughin, B. A., Lauffenburger, D. A. & White, F. M. Multiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition. Nat. Commun. 11, 2760 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Weigelin, B. et al. Cytotoxic T cells are able to efficiently eliminate cancer cells by additive cytotoxicity. Nat. Commun. 12, 5217 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Kumar, M. P. et al. Analysis of single-cell RNA-seq identifies cell-cell communication associated with tumor characteristics. Cell Rep. 25, 1458–1468.e4 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Strasser, S. D. et al. Substrate-based kinase activity inference identifies MK2 as driver of colitis. Integr. Biol. 11, 301–314 (2019).

    Google Scholar 

  189. Gritsenko, P. G. et al. p120-catenin-dependent collective brain infiltration by glioma cell networks. Nat. Cell Biol. 22, 97–107 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Al-Lazikani, B., Banerji, U. & Workman, P. Combinatorial drug therapy for cancer in the post-genomic era. Nat. Biotechnol. 30, 679–692 (2012).

    CAS  PubMed  Google Scholar 

  191. Brubaker, D. K. et al. Proteogenomic network analysis of context-specific KRAS signaling in mouse-to-human cross-species translation. Cell Syst. 9, 258–270.e6 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Na, T.-Y., Schecterson, L., Mendonsa, A. M. & Gumbiner, B. M. The functional activity of E-cadherin controls tumor cell metastasis at multiple steps. Proc. Natl Acad. Sci. USA 117, 5931–5937 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Santis, G. D., Miotti, S., Mazzi, M., Canevari, S. & Tomassetti, A. E-cadherin directly contributes to PI3K/AKT activation by engaging the PI3K-p85 regulatory subunit to adherens junctions of ovarian carcinoma cells. Oncogene 28, 1206–1217 (2009).

    PubMed  Google Scholar 

  194. Kim, N.-G., Koh, E., Chen, X. & Gumbiner, B. M. E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components. Proc. Natl Acad. Sci. USA 108, 11930–11935 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Liu, X. et al. Homophilic CD44 interactions mediate tumor cell aggregation and polyclonal metastasis in patient-derived breast cancer models. Cancer Discov. 9, 96–113 (2019).

    PubMed  Google Scholar 

  196. Wong, C. W., Dye, D. E. & Coombe, D. R. The role of immunoglobulin superfamily cell adhesion molecules in cancer metastasis. Int. J. Cell Biol. 2012, 340296 (2012).

    Google Scholar 

  197. Osswald, M. et al. Brain tumour cells interconnect to a functional and resistant network. Nature 528, 93–98 (2015).

    CAS  PubMed  Google Scholar 

  198. Senbanjo, L. T. & Chellaiah, M. A. CD44: a multifunctional cell surface adhesion receptor is a regulator of progression and metastasis of cancer cells. Front. Cell Dev. Biol. 5, 18 (2017).

    PubMed  PubMed Central  Google Scholar 

  199. Thorne, R. F., Legg, J. W. & Isacke, C. M. The role of the CD44 transmembrane and cytoplasmic domains in co-ordinating adhesive and signalling events. J. Cell Sci. 117, 373–380 (2004).

    CAS  PubMed  Google Scholar 

  200. Nam, K., Oh, S., Lee, K., Yoo, S. & Shin, I. CD44 regulates cell proliferation, migration, and invasion via modulation of c-Src transcription in human breast cancer cells. Cell Signal. 27, 1882–1894 (2015).

    CAS  PubMed  Google Scholar 

  201. Itoh, Y. Discoidin domain receptors: Microenvironment sensors that promote cellular migration and invasion. Cell Adhes. Migr. 4, 378–385 (2018).

    Google Scholar 

  202. Zhang, K. et al. The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. Nat. Cell Biol. 15, 677–687 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Labernadie, A. et al. A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion. Nat. Cell Biol. 19, 224–237 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Ortiz-Otero, N., Marshall, J. R., Lash, B. & King, M. R. Chemotherapy-induced release of circulating-tumor cells into the bloodstream in collective migration units with cancer-associated fibroblasts in metastatic cancer patients. BMC Cancer 20, 873 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Satake, T. et al. Color-coded imaging of the circulating tumor cell microenvironment. Anticancer. Res. 38, 5635–5638 (2018).

    CAS  PubMed  Google Scholar 

  206. Ao, Z. et al. Identification of cancer-associated fibroblasts in circulating blood from patients with metastatic breast cancer. Cancer Res. 75, 4681–4687 (2015).

    CAS  PubMed  Google Scholar 

  207. Chen, Q., Zhang, X. H.-F. & Massagué, J. Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell 20, 538–549 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The original work underlying this article in the authors’ laboratories was supported by the Netherlands Science Organization (NWO-VICI 918.11.626), the European Research Council (617430-DEEPINSIGHT), NIH U54 CA210184-01 and U54 CA261694-01, and the Dutch Cancer Genomics Center (cancergenomics.nl).

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Supplementary information

Glossary

Adaptive resistance

Resistance resulting from stress programmes induced in cancer cells by a range of external triggers, including therapy stress, metabolic perturbation, and cytokine-mediated stemness or epithelial-to-mesenchymal transition.

Anoikis

A form of programmed cell death of anchorage-dependent cells that is activated upon detachment from the extracellular matrix due to the lack of growth and survival signals provided from the matrix interaction.

Autophagy

A controlled pathway in which autophagosomes engulf and degrade cellular organelles as an alternative source for energy production and cell survival.

Cell detritus

Interstitial cell fragments, including cell membranes, organelles and DNA.

Chromatin organization

The 3D structure of DNA, under the control of histone proteins. The density of chromatin packaging determines the accessibility of the genome to transcription factors.

Context receptors

A heterogeneous group of cell surface receptors that provide intracellular signals in response to binding extracellular matrix, matrix-associated growth factors and adjacent cell-surface receptors.

DNA methyltransferases

(DNMTs). A group of enzymes that introduce methylation of cytosine and guanine-rich regions of the DNA and repress transcription by recruitment of methyl-CpG-binding proteins.

Endosomal sorting complexes required for transport III

(ESCRTIII). A complex of cytosolic proteins forming a machinery able to remodel and repair cell membranes.

Epithelial-to-mesenchymal transition

(EMT). The conversion of polarized, adherent epithelial cells into motile mesenchymal cells that lack apicobasal polarity and possess decreased cell–cell adhesion strength and acquire stem cell-like traits.

Hippo pathway

A mechanosensitive pathway that controls cell size, division and apoptosis. In morphogenesis, Hippo pathway activation limits growth and induces apoptosis, whereas in cancer cells it enhances oncogenic signalling.

Histone acetyltransferases

(HATs). A group of enzymes that add acetyl groups to the histone tail; this weakens the strength of binding to DNA, reduces chromatin density and facilitates access of transcription factors to DNA.

Histone deacetylases

(HDACs). A group of enzymes that remove acetyl groups from the histone tail; this strengthens the histone–DNA interaction, leads to chromatin condensation and reduces transcription.

Histone demethylases

(HDMs). A group of enzymes that remove methyl groups from the histone tail, which reduces chromatin density.

Histone methyltransferases

(HMTs). A group of enzymes that add methyl groups to the histone tail, which favours heterochromatization by recruitment of chromatin-binding proteins, which increases chromatin density, decreases DNA accessibility and silences transcription.

Histone-modifying enzymes

Enzymes that induce reversible acetylation and methylation of histones, which regulates the chromatin structure and density, and thereby the local accessibility of DNA for transcription factors and DNA damage response proteins.

Integrin

Adhesion receptor, which engages with extracellular matrix and other ligands and mechanically connects to the actin cytoskeleton for cell anchorage and migration.

Lipid mediators

Metabolites of polyunsaturated fatty acids, including leukotrienes and prostaglandins, which are acutely released by leukocytes to induce and regulate local inflammation.

Matrix metalloproteinases

(MMPs). A large family of proteolytic secreted or membrane-bound enzymes that degrade a broad range of substrates, including extracellular matrix, growth factors and surface receptors.

Nanolumenal release

Extracellular secretion of vesicle content into very tight spaces between cell–cell junctions, which limits dilution of released cytokines and enables particularly strong autocrine and juxtacrine signalling.

Senescence

A cellular state of sustained growth arrest in response to stress. It is associated with increased resistance to cell death.

Shear stress

The physical force exerted on circulating tumour cells by blood flow.

Survivin

Belongs to the inhibitor of apoptosis (IAP) protein family, which inhibits caspases and thereby suppresses apoptosis.

Tissue inhibitor of metalloproteinases 3

(TIMP3). An important broad-spectrum inhibitor of matrix metalloproteinases produced by tumour and stromal cells that inhibits epithelial-to-mesenchymal transition and metastatic progression.

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Weiss, F., Lauffenburger, D. & Friedl, P. Towards targeting of shared mechanisms of cancer metastasis and therapy resistance. Nat Rev Cancer 22, 157–173 (2022). https://doi.org/10.1038/s41568-021-00427-0

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