Sub–Tumor Microenvironments Influence PDAC Progression and Therapy Response

The tumor microenvironment (TME) is critical for tumor progression across a wide range of different cancers and is composed of multiple cell types, including immune cells, endothelial cells, and cancer-associated fibroblasts (CAF). The nuances behind the variation of these stromal elements and how this ultimately affects disease progression continue to be not fully understood. Grünwald and colleagues sought to identify recurrent regional histologic patterns in pancreatic ductal adenocarcinoma (PDAC), which is known for its complex TME. Regional TME heterogeneity was attributed to variations in the ratios of cellular to acellular components. Two major phenotypes were subsequently described, the first of which was termed “deserted” and is defined as matrix rich, as indicated by its high collagen content, and featured fewer fibroblasts. The second phenotype, also called the “reactive” phenotype, is characterized by functional fibroblasts, an abundance of immune cells including T cells and macrophages, as well as an aggressive tumor cell phenotype. The CAF populations between these two subtypes were also distinct, both phenotypically and behaviorally, with those from the reactive TME being more motile, while those from the deserted subtype were more proliferative. Additionally, these different subtypes appear to arise from complex CAF communities with specific phenotypes, behaviors, and functions. Furthermore, these sub-TMEs can co-occur in the same tumor in a spatially confined manner, with the presence of this heterogeneous TME leading to poorer prognosis in patients. Analyses of the effects of these sub-TMEs on PDAC tumor progression indicated that the reactive TME state promoted tumor progression through stimulation of proliferation and a dedifferentiated tumor phenotype. Conversely, the deserted TME subtype was found to be chemoprotective, and chemotherapy promoted a more desert-like composition within tumors. The results of this study point to functional intratumoral heterogeneity of the PDAC TME and aid in understanding its relevance in disease progression with the hopes of developing future biomarkers and stromal targets.

Grünwald, BT, Devisme A, Andrieux G, Vyas F, Aliar K, McCloskey CW, et al. Spatially confined sub-tumor microenvironments in pancreatic cancer. Cell 2021;184(22):5577–92.

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