Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Pancreatic cancer stroma: an update on therapeutic targeting strategies

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the Western world with limited therapeutic options and dismal long-term survival. The neoplastic epithelium exists within a dense stroma, which is recognized as a critical mediator of disease progression through direct effects on cancer cells and indirect effects on the tumour immune microenvironment. The three dominant entities in the PDAC stroma are extracellular matrix (ECM), vasculature and cancer-associated fibroblasts (CAFs). The ECM can function as a barrier to effective drug delivery to PDAC cancer cells, and a multitude of strategies to target the ECM have been attempted in the past decade. The tumour vasculature is a complex system and, although multiple anti-angiogenesis agents have already failed late-stage clinical trials in PDAC, other vasculature-targeting approaches aimed at vessel normalization and tumour immunosensitization have shown promise in preclinical models. Lastly, PDAC CAFs participate in active cross-talk with cancer cells within the tumour microenvironment. The existence of intratumoural CAF heterogeneity represents a paradigm shift in PDAC CAF biology, with myofibroblastic and inflammatory CAF subtypes that likely make distinct contributions to PDAC progression. In this Review, we discuss our current understanding of the three principal constituents of PDAC stroma, their effect on the prevalent immune landscape and promising therapeutic targets within this compartment.

Key points

  • The tumour microenvironment of pancreatic ductal adenocarcinoma (PDAC) is composed of extracellular matrix (ECM) proteins, tumour vasculature, fibroblasts and immune cells.

  • ECM proteins in PDAC can increase intratumoural pressure and act as a barrier to effective drug delivery to the tumour. Clinical trials have aimed to exploit this understanding of the PDAC ECM but have so far failed to show an improvement in patient survival.

  • Tumour-associated vasculature has been shown to be important for PDAC disease pathogenesis in preclinical models; however, clinical trials aimed at targeting the PDAC vasculature have not prolonged patient survival.

  • Pruning PDAC vasculature (normalization) might present a strategy for improved chemotherapy delivery and host antitumour immune responses.

  • Molecular subtypes of pancreatic cancer-associated fibroblasts (CAFs) have been described, most notably inflammatory CAFs and myofibroblastic CAFs, which have been postulated to demonstrate protumour and antitumour properties, respectively.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The desmoplastic response is a key feature in human and mouse PDAC.
Fig. 2: Therapeutic targets in the extracellular matrix of PDAC.
Fig. 3: Vascular normalization as a therapeutic strategy in PDAC.
Fig. 4: Immunohistochemical analysis of pancreatic ductal adenocarcinoma CAF subtypes.
Fig. 5: Intratumoural fibroblast heterogeneity in PDAC.
Fig. 6: Therapeutic targets in PDAC CAFs.

Similar content being viewed by others

References

  1. American Cancer Society. Facts and Figures (American Cancer Society, 2019).

  2. Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).

    PubMed  Google Scholar 

  3. Li, D. et al. Pancreatic cancer. Lancet 363, 1049–1057 (2004).

    CAS  PubMed  Google Scholar 

  4. Conroy, T. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364, 1817–1825 (2011).

    CAS  PubMed  Google Scholar 

  5. Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691–1703 (2013).

    Google Scholar 

  6. Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Drilon, A. et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N. Engl. J. Med. 378, 731–739 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Golan, T. et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N. Engl. J. Med. 381, 317–327 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).

    CAS  PubMed  Google Scholar 

  11. The Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32, 185–203 (2017).

    PubMed Central  Google Scholar 

  12. Collisson, E. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat. Med. 17, 500–503 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Moffitt, R. A. et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet. 47, 1168–78 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Nicolle, R. et al. Pancreatic adenocarcinoma therapeutic targets revealed by tumor-stroma cross-talk analyses in patient-derived xenografts. Cell Rep. 21, 2458–2470 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Puleo, F. et al. Stratification of pancreatic ductal adenocarcinomas based on tumor and microenvironment features. Gastroenterology 155, 1999–2013 (2018).

    PubMed  Google Scholar 

  16. Binkley, C. E. et al. The molecular basis of pancreatic fibrosis: common stromal gene expression in chronic pancreatitis and pancreatic adenocarcinoma. Pancreas 29, 254–263 (2004).

    CAS  PubMed  Google Scholar 

  17. Bachem, M. G. et al. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 128, 907–921 (2005).

    CAS  PubMed  Google Scholar 

  18. Armstrong, T. et al. Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Clin. Cancer Res. 10, 7427–7437 (2004).

    CAS  PubMed  Google Scholar 

  19. Apte, M. V. et al. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas 29, 179–187 (2004).

    CAS  PubMed  Google Scholar 

  20. Bonnans, C., Chou, J. & Werb, Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 15, 786–801 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Linder, S. et al. Immunohistochemical expression of extracellular matrix proteins and adhesion molecules in pancreatic carcinoma. Hepatogastroenterology 48, 1321–1327 (2001).

    CAS  PubMed  Google Scholar 

  22. Ohlund, D. et al. Type IV collagen is a tumour stroma-derived biomarker for pancreas cancer. Br. J. Cancer 101, 91–97 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Whatcott, C. J. et al. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin. Cancer Res. 21, 3561–3568 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhong, Y. et al. Mutant p53 together with TGFbeta signaling influence organ-specific hematogenous colonization patterns of pancreatic cancer. Clin. Cancer Res. 23, 1607–1620 (2017).

    CAS  PubMed  Google Scholar 

  25. Ohlund, D. et al. Type IV collagen stimulates pancreatic cancer cell proliferation, migration, and inhibits apoptosis through an autocrine loop. BMC Cancer 13, 154 (2013).

    PubMed  PubMed Central  Google Scholar 

  26. Laklai, H. et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat. Med. 22, 497–505 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Desgrosellier, J. S. & Cheresh, D. A. Integrins in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer 10, 9–22 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Grzesiak, J. J. et al. Knockdown of the beta1 integrin subunit reduces primary tumor growth and inhibits pancreatic cancer metastasis. Int. J. Cancer 129, 2905–2915 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Nagathihalli, N. S. et al. Signal transducer and activator of transcription 3, mediated remodeling of the tumor microenvironment results in enhanced tumor drug delivery in a mouse model of pancreatic cancer. Gastroenterology 149, 1932–1943 (2015).

    CAS  PubMed  Google Scholar 

  30. Ji, T. et al. Designing liposomes to suppress extracellular matrix expression to enhance drug penetration and pancreatic tumor therapy. ACS Nano 11, 8668–8678 (2017).

    CAS  PubMed  Google Scholar 

  31. Iyer, S. N., Gurujeyalakshmi, G. & Giri, S. N. Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J. Pharmacol. Exp. Ther. 291, 367–373 (1999).

    CAS  PubMed  Google Scholar 

  32. Iyer, S. N., Gurujeyalakshmi, G. & Giri, S. N. Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J. Pharmacol. Exp. Ther. 289, 211–218 (1999).

    CAS  PubMed  Google Scholar 

  33. Diop-Frimpong, B. et al. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc. Natl Acad. Sci. USA 108, 2909–2914 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Murphy, J. E. et al. Total neoadjuvant therapy with FOLFIRINOX in combination with losartan followed by chemoradiotherapy for locally advanced pancreatic cancer: a phase 2 clinical trial. JAMA Oncol. 5, 1020–1027 (2019).

    PubMed  PubMed Central  Google Scholar 

  35. Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Thompson, C. B. et al. Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical animal models. Mol. Cancer Ther. 9, 3052–3064 (2010).

    CAS  PubMed  Google Scholar 

  37. Jacobetz, M. A. et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62, 112–120 (2013).

    CAS  PubMed  Google Scholar 

  38. Chauhan, V. P. et al. Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fluid pressure. Cancer Cell 26, 14–15 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. DuFort, C. C. et al. Interstitial pressure in pancreatic ductal adenocarcinoma is dominated by a gel-fluid phase. Biophys. J. 110, 2106–2119 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Hunger, J. et al. Hydration dynamics of hyaluronan and dextran. Biophys. J. 103, L10–L12 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Ramanathan, R. K. et al. Phase IB/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase versus FOLFIRINOX alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313. J. Clin. Oncol. 37, 1062–1069 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02715804 (2019).

  43. Tempero, M. et al. HALO 109-301: A randomized, double-blind, placebo-controlled, phase 3 study of pegvorhyaluronidase alfa (PEGPH20) + nab-paclitaxel/gemcitabine (AG) in patients (pts) with previously untreated hyaluronan (HA)-high metastatic pancreatic ductal adenocarcinoma (mPDA). J. Clin. Oncol. 38 (Suppl. 4), 638 (2020).

    Google Scholar 

  44. Halozyme Therapeutics. Halozyme announces HALO-301 phase 3 study fails to meet primary endpoint Halozyme.com https://www.halozyme.com/investors/news-releases/news-release-details/2019/Halozyme-Announces-HALO-301-Phase-3-Study-Fails-To-Meet-Primary-Endpoint/default.aspx (2019).

  45. Kamphorst, J. J. et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75, 544–553 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Davidson, S. M. et al. Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors. Nat. Med. 23, 235–241 (2017).

    CAS  PubMed  Google Scholar 

  47. Olivares, O. et al. Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nat. Commun. 8, 16031 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Scott, G. K. et al. Targeting the mitochondrial enzyme proline dehydrogenase with a mechanism-based irreversible inhibitor induces selective mitochondrial stress and enhances breast cancer cell death under hypoxia [abstract]. Cancer Res. 77 (Suppl.), 1489 (2017).

    Google Scholar 

  49. Rath, N. & Olson, M. F. Rho-associated kinases in tumorigenesis: re-considering ROCK inhibition for cancer therapy. EMBO Rep. 13, 900–908 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Rath, N. et al. ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth. EMBO Mol. Med. 9, 198–218 (2017).

    CAS  PubMed  Google Scholar 

  51. Vennin, C. et al. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Sci. Transl. Med. 9, eaai8504 (2017).

    PubMed  PubMed Central  Google Scholar 

  52. Stokes, J. B. et al. Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment. Mol. Cancer Ther. 10, 2135–2145 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Jiang, H. et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat. Med. 22, 851–860 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02546531 (2019).

  55. Wang-Gillam, A. L. A. et al. Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer. J. Clin. Oncol. 36 (Suppl. 4), 380 (2018).

    Google Scholar 

  56. Shintani, Y. et al. Collagen I promotes metastasis in pancreatic cancer by activating c-Jun NH2-terminal kinase 1 and up-regulating N-cadherin expression. Cancer Res. 66, 11745–11753 (2006).

    CAS  PubMed  Google Scholar 

  57. Shintani, Y. et al. Collagen I-mediated up-regulation of N-cadherin requires cooperative signals from integrins and discoidin domain receptor 1. J. Cell Biol. 180, 1277–1289 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Huang, H. et al. Up-regulation of N-cadherin by collagen I-activated discoidin domain receptor 1 in pancreatic cancer requires the adaptor molecule Shc1. J. Biol. Chem. 291, 23208–23223 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Zheng, X. et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525–530 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Aiello, N. M. et al. Upholding a role for EMT in pancreatic cancer metastasis. Nature 547, E7–E8 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Aiello, N. M. et al. EMT subtype influences epithelial plasticity and mode of cell migration. Dev. Cell 45, 681–695 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Aguilera, K. Y. et al. Inhibition of discoidin domain receptor 1 reduces collagen-mediated tumorigenicity in pancreatic ductal adenocarcinoma. Mol. Cancer Ther. 16, 2473–2485 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Hur, H. et al. Discoidin domain receptor 1 activity drives an aggressive phenotype in gastric carcinoma. BMC Cancer 17, 87 (2017).

    PubMed  PubMed Central  Google Scholar 

  64. Ambrogio, C. et al. Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma. Nat. Med. 22, 270–277 (2016).

    CAS  PubMed  Google Scholar 

  65. Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).

    CAS  PubMed  Google Scholar 

  66. Ezzell, C. Starving tumors of their lifeblood. Sci. Am. 279, 33–34 (1998).

    CAS  PubMed  Google Scholar 

  67. Ferrara, N. et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat. Rev. Drug. Discov. 3, 391–400 (2004).

    CAS  PubMed  Google Scholar 

  68. Di Maggio, F. et al. Pancreatic stellate cells regulate blood vessel density in the stroma of pancreatic ductal adenocarcinoma. Pancreatology 16, 995–1004 (2016).

    PubMed  Google Scholar 

  69. Nishida, T. et al. Low stromal area and high stromal microvessel density predict poor prognosis in pancreatic cancer. Pancreas 45, 593–600 (2016).

    CAS  PubMed  Google Scholar 

  70. Ikeda, N. et al. Prognostic significance of angiogenesis in human pancreatic cancer. Br. J. Cancer 79, 1553–1563 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Itakura, J. et al. Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. Clin. Cancer Res. 3, 1309–1316 (1997).

    CAS  PubMed  Google Scholar 

  72. Buchler, P. et al. Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human pancreatic cancer. Pancreas 26, 56–64 (2003).

    CAS  PubMed  Google Scholar 

  73. Wei, D. et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 22, 319–329 (2003).

    CAS  PubMed  Google Scholar 

  74. Shibaji, T. et al. Prognostic significance of HIF-1 alpha overexpression in human pancreatic cancer. Anticancer Res. 23, 4721–4727 (2003).

    CAS  PubMed  Google Scholar 

  75. Luo, J. et al. Pancreatic cancer cell-derived vascular endothelial growth factor is biologically active in vitro and enhances tumorigenicity in vivo. Int. J. Cancer 92, 361–369 (2001).

    CAS  PubMed  Google Scholar 

  76. Fukasawa, M. & Korc, M. Vascular endothelial growth factor-trap suppresses tumorigenicity of multiple pancreatic cancer cell lines. Clin. Cancer Res. 10, 3327–3332 (2004).

    CAS  PubMed  Google Scholar 

  77. Bockhorn, M. et al. Differential vascular and transcriptional responses to anti-vascular endothelial growth factor antibody in orthotopic human pancreatic cancer xenografts. Clin. Cancer Res. 9, 4221–4226 (2003).

    CAS  PubMed  Google Scholar 

  78. Kindler, H. L. et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J. Clin. Oncol. 23, 8033–8040 (2005).

    CAS  PubMed  Google Scholar 

  79. Kindler, H. L. et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J. Clin. Oncol. 28, 3617–3622 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Van Cutsem, E. et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J. Clin. Oncol. 27, 2231–2237 (2009).

    PubMed  Google Scholar 

  81. Rougier, P. et al. Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. Eur. J. Cancer 49, 2633–2642 (2013).

    CAS  PubMed  Google Scholar 

  82. Hu-Lowe, D. D. et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin. Cancer Res. 14, 7272–7283 (2008).

    CAS  PubMed  Google Scholar 

  83. Kindler, H. L. et al. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 12, 256–62 (2011).

    CAS  PubMed  Google Scholar 

  84. Wilhelm, S. M. et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64, 7099–7109 (2004).

    CAS  PubMed  Google Scholar 

  85. Goncalves, A. et al. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann. Oncol. 23, 2799–805 (2012).

    CAS  PubMed  Google Scholar 

  86. Infante, J. R. et al. Lenalidomide in combination with gemcitabine as first-line treatment for patients with metastatic carcinoma of the pancreas: a Sarah Cannon Research Institute phase II trial. Cancer Biol. Ther. 14, 340–346 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Pennacchietti, S. et al. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3, 347–361 (2003).

    PubMed  Google Scholar 

  88. Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Paez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220–231 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Conley, S. J. et al. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc. Natl Acad. Sci. USA 109, 2784–2789 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Carbone, C. et al. Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype. Clin. Cancer Res. 17, 5822–5832 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Aguilera, K. Y. et al. Collagen signaling enhances tumor progression after anti-VEGF therapy in a murine model of pancreatic ductal adenocarcinoma. Cancer Res. 74, 1032–1044 (2014).

    CAS  PubMed  Google Scholar 

  93. Jain, R. K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med. 7, 987–989 (2001).

    CAS  PubMed  Google Scholar 

  94. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

    CAS  PubMed  Google Scholar 

  95. Goel, S., Wong, A. H. & Jain, R. K. Vascular normalization as a therapeutic strategy for malignant and nonmalignant disease. Cold Spring Harb. Perspect. Med. 2, a006486 (2012).

    PubMed  PubMed Central  Google Scholar 

  96. Galluzzo, M. et al. Prevention of hypoxia by myoglobin expression in human tumor cells promotes differentiation and inhibits metastasis. J. Clin. Invest. 119, 865–75 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Serini, G. et al. Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 424, 391–397 (2003).

    CAS  PubMed  Google Scholar 

  98. Maione, F. et al. Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. J. Clin. Invest. 119, 3356–3372 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Casazza, A. et al. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24, 695–709 (2013).

    CAS  PubMed  Google Scholar 

  100. Gioelli, N. et al. A rationally designed NRP1-independent superagonist SEMA3A mutant is an effective anticancer agent. Sci. Transl. Med. 10, eaah4807 (2018)

    PubMed  Google Scholar 

  101. Gilles, M. E. et al. Nucleolin targeting impairs the progression of pancreatic cancer and promotes the normalization of tumor vasculature. Cancer Res. 76, 7181–7193 (2016).

    CAS  PubMed  Google Scholar 

  102. Conroy, T. et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N. Engl. J. Med. 379, 2395–2406 (2018).

    CAS  PubMed  Google Scholar 

  103. Murphy, J. E. et al. Total neoadjuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: a phase 2 clinical trial. JAMA Oncol. 4, 963–969 (2018).

    PubMed  PubMed Central  Google Scholar 

  104. Barsoum, I. B. et al. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 74, 665–674 (2014).

    CAS  PubMed  Google Scholar 

  105. Raggi, F. et al. Regulation of human macrophage M1-M2 polarization balance by hypoxia and the triggering receptor expressed on myeloid cells-1. Front. Immunol. 8, 1097 (2017).

    PubMed  PubMed Central  Google Scholar 

  106. Huang, Y. et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc. Natl Acad. Sci. USA 109, 17561–17566 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Kabacaoglu, D. Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: current limitations and future options. Front. Immunol. 9, 1878 (2018).

    PubMed  PubMed Central  Google Scholar 

  108. Roland, C. L. et al. Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer. PLoS One 4, e7669 (2009).

    PubMed  PubMed Central  Google Scholar 

  109. Ohm, J. E. et al. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood 101, 4878–4886 (2003).

    CAS  PubMed  Google Scholar 

  110. Gabrilovich, D. I. et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med. 2, 1096–1103 (1996).

    CAS  PubMed  Google Scholar 

  111. Griffioen, A. W. et al. Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium. Blood 88, 667–673 (1996).

    CAS  PubMed  Google Scholar 

  112. Shrimali, R. K. et al. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 70, 6171–6180 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Tian, L. et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544, 250–254 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Zhang, Y. et al. Cyclooxygenase-2 inhibition potentiates the efficacy of vascular endothelial growth factor blockade and promotes an immune stimulatory microenvironment in preclinical models of pancreatic cancer. Mol. Cancer Res. 17, 348–355 (2019).

    CAS  PubMed  Google Scholar 

  115. Rinn, J. L. et al. Anatomic demarcation by positional variation in fibroblast gene expression programs. PLoS Genet. 2, e119 (2006).

    PubMed  PubMed Central  Google Scholar 

  116. Lynch, M. D. & Watt, F. M. Fibroblast heterogeneity: implications for human disease. J. Clin. Invest. 128, 26–35 (2018).

    PubMed  PubMed Central  Google Scholar 

  117. Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).

    CAS  PubMed  Google Scholar 

  118. Hwang, R. F. et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 68, 918–926 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Özdemir, B. C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014).

    PubMed  PubMed Central  Google Scholar 

  120. Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Ohlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214, 579–596 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Omary, M. B. et al. The pancreatic stellate cell: a star on the rise in pancreatic diseases. J. Clin. Invest. 117, 50–59 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Bernard, V. et al. Single-cell transcriptomics of pancreatic cancer precursors demonstrates epithelial and microenvironmental heterogeneity as an early event in neoplastic progression. Clin. Cancer Res. 25, 2194–2205 (2018).

    PubMed  PubMed Central  Google Scholar 

  124. Biffi, G. et al. IL1-induced JAK/STAT signaling is antagonized by TGFbeta to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 9, 282–301 (2019).

    PubMed  Google Scholar 

  125. Shi, Y. et al. Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Nature 569, 131–135 (2018).

    Google Scholar 

  126. Huang, H. et al. Targeting TGFbetaR2-mutant tumors exposes vulnerabilities to stromal TGFbeta blockade in pancreatic cancer. EMBO Mol. Med. 11, e10515 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102–1123 (2019).

    PubMed  PubMed Central  Google Scholar 

  128. Hosein, A. N. et al. Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution. JCI Insight 5, e129212 (2019).

    Google Scholar 

  129. Barnden, M. J. et al. Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements. Immunol. Cell Biol. 76, 34–40 (1998).

    CAS  PubMed  Google Scholar 

  130. Dominguez, C. X. et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15+ myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Discov. 10, 232–253 (2019).

    PubMed  Google Scholar 

  131. Ligorio, M. et al. Stromal microenvironment shapes the intratumoral architecture of pancreatic cancer. Cell 178, 160–175 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Erez, N. et al. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell 17, 135–147 (2010).

    CAS  PubMed  Google Scholar 

  133. Zhang, Q., Lenardo, M. J. & Baltimore, D. 30 years of NF-kappaB: a blossoming of relevance to human pathobiology. Cell 168, 37–57 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Biffi, G. et al. IL-1-induced JAK/STAT signaling is antagonized by TGF-beta to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 9, 282–301 (2018).

    PubMed  PubMed Central  Google Scholar 

  135. Zhang, D. et al. Tumor-stroma IL1beta-IRAK4 feedforward circuitry drives tumor fibrosis, chemoresistance, and poor prognosis in pancreatic cancer. Cancer Res. 78, 1700–1712 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. US National Library of Medicine. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT02021422 (2017).

  137. Hurwitz, H. et al. Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies. Invest. N. Drugs 36, 683–695 (2018).

    CAS  Google Scholar 

  138. Djurec, M. et al. Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors. Proc. Natl Acad. Sci. USA 115, E1147–E1156 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. US National Library of Medicine. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT03086369 (2020).

  140. Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Garg, B. et al. NFkappaB in pancreatic stellate cells reduces infiltration of tumors by cytotoxic T cells and killing of cancer cells, via up-regulation of CXCL12. Gastroenterology 155, 880–891 (2018).

    CAS  PubMed  Google Scholar 

  142. US National Library of Medicine. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT03168139 (2019).

  143. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02826486 (2020).

  144. Hidalgo, M. et al. A multi-center phase IIa trial to assess the safety and efficacy of BL-8040 (a CXCR4 inhibitor) in combination with pembrolizumab and chemotherapy in patients with metastatic pancreatic adenocarcinoma (PDAC). Ann. Oncol. 30 (Suppl. 11) 33 (2019).

    Google Scholar 

  145. Nagathihalli, N. S. et al. Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells. Oncotarget 7, 65982–65992 (2016).

    PubMed  PubMed Central  Google Scholar 

  146. Long, K. B. et al. IL6 receptor blockade enhances chemotherapy efficacy in pancreatic ductal adenocarcinoma. Mol. Cancer Ther. 16, 1898–1908 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Kim, H. W. et al. Serum interleukin-6 is associated with pancreatic ductal adenocarcinoma progression pattern. Medicine 96, e5926 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Lee, J. W. et al. Hepatocytes direct the formation of a pro-metastatic niche in the liver. Nature 567, 249–252 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Maitra, A. Molecular envoys pave the way for pancreatic cancer to invade the liver. Nature 567, 181–182 (2019).

    CAS  PubMed  Google Scholar 

  150. US National Library of Medicine. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT02767557 (2019).

  151. Goumas, F. A. et al. Inhibition of IL-6 signaling significantly reduces primary tumor growth and recurrencies in orthotopic xenograft models of pancreatic cancer. Int. J. Cancer 137, 1035–1046 (2015).

    CAS  PubMed  Google Scholar 

  152. Mitsunaga, S. et al. Multicenter, open-label, phase I/II study of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, combined with gemcitabine in patients with advanced pancreatic cancer. J. Med. Diagn. Methods 6, 1000234 (2017).

    Google Scholar 

  153. Flint, T. R. et al. Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity. Cell Metab. 24, 672–684 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Mace, T. A. et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut 67, 320–332 (2018).

    CAS  PubMed  Google Scholar 

  155. US National Library of Medicine. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04191421 (2020).

  156. Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005).

    CAS  PubMed  Google Scholar 

  157. Bailey, J. M. et al. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin. Cancer Res. 14, 5995–6004 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Lee, J. J. et al. Stromal response to hedgehog signaling restrains pancreatic cancer progression. Proc. Natl Acad. Sci. USA 111, E3091–E3100 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Catenacci, D. V. et al. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J. Clin. Oncol. 33, 4284–4292 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Ko, A. H. et al. A phase I study of FOLFIRINOX plus IPI-926, a hedgehog pathway inhibitor, for advanced pancreatic adenocarcinoma. Pancreas 45, 370–375 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Sinn, M. et al. α-smooth muscle actin expression and desmoplastic stromal reaction in pancreatic cancer: results from the CONKO-001 study. Br. J. Cancer 111, 1917–1923 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Quante, M. et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 19, 257–272 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Direkze, N. C. et al. Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res. 64, 8492–8495 (2004).

    CAS  PubMed  Google Scholar 

  164. Spaeth, E. L. et al. Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS One 4, e4992 (2009).

    PubMed  PubMed Central  Google Scholar 

  165. Karnoub, A. E. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557–563 (2007).

    CAS  PubMed  Google Scholar 

  166. Waghray, M. et al. GM-CSF mediates mesenchymal-epithelial cross-talk in pancreatic cancer. Cancer Discov. 6, 886–899 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Bayne, L. J. et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21, 822–835 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Pylayeva-Gupta, Y. et al. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21, 836–847 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Takeuchi, S. et al. Chemotherapy-derived inflammatory responses accelerate the formation of immunosuppressive myeloid cells in the tissue microenvironment of human pancreatic cancer. Cancer Res. 75, 2629–2640 (2015).

    CAS  PubMed  Google Scholar 

  170. Wainberg, Z. A. et al. First-in-human phase 1 dose escalation and expansion of a novel combination, anti-CSF-1 receptor (cabiralizumab) plus anti-PD-1 (nivolumab), in patients with advanced solid tumors. Society for Immunotherapy of Cancer https://doi.org/10.13140/RG.2.2.28962.53443 (2019).

    Article  Google Scholar 

  171. Tape, C. J. et al. Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation. Cell 165, 910–992 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Ludwig, K. F. et al. Small-molecule inhibition of AXL targets tumor immune suppression and enhances chemotherapy in pancreatic cancer. Cancer Res. 78, 246–255 (2018).

    CAS  PubMed  Google Scholar 

  173. Ireland, L. et al. Chemoresistance in pancreatic cancer is driven by stroma-derived insulin-like growth factors. Cancer Res. 76, 6851–6863 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Rucki, A. A. et al. Heterogeneous stromal signaling within the tumor microenvironment controls the metastasis of pancreatic cancer. Cancer Res. 77, 41–52 (2017).

    CAS  PubMed  Google Scholar 

  175. Fuchs, C. S. et al. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann. Oncol. 26, 921–927 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Kundranda, M. et al. Randomized, double-blind, placebo-controlled phase II study of istiratumab (MM-141) plus nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine in front-line metastatic pancreatic cancer (CARRIE). Ann. Oncol. 31, 79–87 (2020).

    CAS  PubMed  Google Scholar 

  177. Carraway, K. L. 3rd et al. The erbB3 gene product is a receptor for heregulin. J. Biol. Chem. 269, 14303–14306 (1994).

    CAS  PubMed  Google Scholar 

  178. Philip, P. A. et al. Dual blockade of epidermal growth factor receptor and insulin-like growth factor receptor-1 signaling in metastatic pancreatic cancer: phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG S0727). Cancer 120, 2980–2985 (2014).

    CAS  PubMed  Google Scholar 

  179. Abdel-Wahab, R. et al. Randomized, phase I/II study of gemcitabine plus IGF-1R antagonist (MK-0646) versus gemcitabine plus erlotinib with and without MK-0646 for advanced pancreatic adenocarcinoma. J. Hematol. Oncol. 11, 71 (2018).

    PubMed  PubMed Central  Google Scholar 

  180. US National Library of Medicine. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT02729298 (2019).

  181. US National Library of Medicine. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT03649321 (2020).

  182. Sherman, M. H. et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159, 80–93 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Kong, F. et al. VDR signaling inhibits cancer-associated-fibroblasts’ release of exosomal miR-10a-5p and limits their supportive effects on pancreatic cancer cells. Gut 68, 950–951 (2019).

    CAS  PubMed  Google Scholar 

  184. Weiss, F. U. et al. Retinoic acid receptor antagonists inhibit miR-10a expression and block metastatic behavior of pancreatic cancer. Gastroenterology 137, 2136–2145.e1–7 (2009).

    CAS  PubMed  Google Scholar 

  185. Van Loon, K., et al. 25-Hydroxyvitamin D levels and survival in advanced pancreatic cancer: findings from CALGB 80303 (Alliance). J. Natl Cancer Inst. 106, dju185 (2014).

    PubMed  PubMed Central  Google Scholar 

  186. US National Library of Medicine. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT03472833 (2019).

  187. US National Library of Medicine. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT03300921 (2020).

  188. Borazanci, E. H. et al. A phase II pilot trial of nivolumab (N) + albumin bound paclitaxel (AP) + paricalcitol (P) + cisplatin (C) + gemcitabine (G) (NAPPCG) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC). J. Clin. Oncol. 36 (Suppl. 4), 358 (2018).

    Google Scholar 

  189. US National Library of Medicine. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT02754726 (2020).

  190. Lo-Coco, F. et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N. Engl. J. Med. 369, 111–121 (2013).

    CAS  PubMed  Google Scholar 

  191. Chronopoulos, A. et al. ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion. Nat. Commun. 7, 12630 (2016).

    PubMed  PubMed Central  Google Scholar 

  192. Sarper, M. et al. ATRA modulates mechanical activation of TGF-beta by pancreatic stellate cells. Sci. Rep. 6, 27639 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Froeling, F. E. et al. Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-beta-catenin signaling to slow tumor progression. Gastroenterology 141, 1486–1497 e1–14 (2011).

    CAS  PubMed  Google Scholar 

  194. Carapuca, E. F. et al. Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma. J. Pathol. 239, 286–296 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Kocher, H. M. et al. 700P - STAR-PAC: phase I clinical trial repurposing all trans retinoic acid (ATRA) as stromal targeting agent in a novel drug combination for pancreatic cancer. Ann. Oncol. 30 (Suppl. 5), 267 (2019).

    Google Scholar 

  196. Matrisian, L. M. & Berlin, J. D. The past, present, and future of pancreatic cancer clinical trials. Am. Soc. Clin. Oncol. Educ. Book 35, e205–e215 (2016).

    PubMed  Google Scholar 

  197. Akashi, Y. et al. Histological advantages of the tumor graft: a murine model involving transplantation of human pancreatic cancer tissue fragments. Pancreas 42, 1275–1282 (2013).

    CAS  PubMed  Google Scholar 

  198. Tiriac, H. et al. Organoid profiling identifies common responders to chemotherapy in pancreatic cancer. Cancer Discov. 8, 1112–1129 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Seino, T. et al. Human pancreatic tumor organoids reveal loss of stem cell niche factor dependence during disease progression. Cell Stem Cell 22, 454–467 (2018).

    CAS  PubMed  Google Scholar 

  200. US National Library of Medicine. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT03307148 (2020).

  201. US National Library of Medicine. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT02399137 (2018).

Download references

Acknowledgements

The authors thank D. Primm (UT Southwestern Medical Center) for help in editing this article and C. Kwak (UT MD Anderson Cancer Center) who provided images of mouse tumours. R.A.B. acknowledges funding from the following sources: NIH grants R01 (CA192381) and U54 (CA210181 Project 2), the Effie Marie Cain Fellowship and the Jean Shelby Fund for Cancer Research at Communities Foundation of Texas. A.M. acknowledges funding from the following sources: NCI U24 CA224020, NCI R01CA218004 and NCI R01CA220236.

Author information

Authors and Affiliations

Authors

Contributions

A.N.H. conceived of and drafted the article; R.A.B and A.M. conceived of and provided editorial guidance.

Corresponding authors

Correspondence to Rolf A. Brekken or Anirban Maitra.

Ethics declarations

Competing interests

A.M. receives royalties from Cosmos Wisdom Biotechnology for a biomarker assay related to early detection of pancreatic cancer. A.M. is an inventor on a patent that has been licensed to Thrive Earlier Detection. The remaining authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Gastroenterology & Hepatology thanks M. Apte, M. Nakamura and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hosein, A.N., Brekken, R.A. & Maitra, A. Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat Rev Gastroenterol Hepatol 17, 487–505 (2020). https://doi.org/10.1038/s41575-020-0300-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41575-020-0300-1

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research