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.

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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.

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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.

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

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Correspondence to Rolf A. Brekken or Anirban Maitra.

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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.

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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.

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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

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