Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance

Abstract

Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance. Recent advances in tissue imaging capabilities, single-cell analytics, and disease modeling have shed light on organizing principles that shape the stromal complexity of PDAC tumors. These insights into the functional and spatial dependencies that coordinate cancer cell biology and the relationships that exist between cells and extracellular matrix components present in tumors are expected to unveil therapeutic vulnerabilities. We review recent advances in the field and discuss current understandings of mechanisms by which the tumor microenvironment shapes PDAC pathogenesis and therapy resistance.

Keywords: cancer-associated fibroblast; pancreatic cancer; stroma; tumor immunology; tumor microenvironment.

Figure 1

The PDAC microenvironment. (a) Schematic of PDAC lesion showing discrete cellular communities and their relationship to tumor regions. (b) Representative images showing hematoxylin and eosin staining (top row) and mIHC (bottom row) of cellular communities depicted in panel a. (c)–(e) Representative mIHC images showing the spatial relationship of cells and matrix elements with cancer cells (CK19). Regions of TA and TS stroma are depicted and separated with a dashed black line. Abbreviations: CC3, cleaved caspase 3; Col I, type I collagen; mIHC, multiplex immunohistochemistry; PDAC, pancreatic ductal adenocarcinoma; SMA, smooth muscle actin; TA, tumor-adjacent; TS tumor-associated.

Figure 2

Spatially defined immune heterogeneity in PDAC. (a) Representative images showing mIHC staining of human PDAC to detect cellular communities that are immune deserted, T cell enriched, and myeloid enriched. (b) Conceptual model depicting a nest of clonally heterogenous cancer cells that upon migration into the stroma give rise to either T cell low or T cell high tumor nests. Shown are representative mIHC images of T cell low and T cell high regions detected in human PDAC. Abbreviations: mIHC, multiplex immunohistochemistry; PDAC, pancreatic ductal adenocarcinoma.