Cancer-Associated Fibroblasts Contribute to PDAC Heterogeneity

The tumor microenvironment comprises a heterogeneous collection of normal and tumor cells, including cancer-associated fibroblasts (CAF). In pancreatic ductal adenocarcinoma (PDAC), this heterogeneity has made it difficult to discern the precise contribution of stromal CAFs to tumor progression and aggressiveness. To better define the role of CAFs in regulating PDAC heterogeneity, Ligorio, Sil, and colleagues performed single-cell RNA sequencing (scRNA-seq) and proteomics in mouse models and patient samples of PDAC. scRNA-seq of patient-derived PDAC and CAF cells cocultured at various ratios revealed two gene signatures contributing to proliferation (PRO) and epithelial–mesenchymal transition (EMT) within PDAC cells, a subpopulation of which coexpressed both signatures (DP) when cultured at the highest CAF:PDAC ratio. Coculturing patient-derived PDAC cell lines with CAFs caused a positive shift toward both PRO and EMT phenotypes with increased proliferation and invasion in vitro and accelerated tumor growth and metastatic tumor burden in vivo. Further, PDAC cell lines exposed to CAF-conditioned media underwent a shift toward the DP phenotype and increased activation of MAPK and STAT3 signaling pathways. Similarly, enrichment of MAPK and STAT3 signaling in the DP population was also observed in primary and metastatic patient PDAC tumors; combined pharmacologic inhibition of these pathways abrogated the DP phenotype and suppressed PDAC cell invasion in vitro. CAF-derived TGF1β was a critical factor for PDAC cell proliferation, as treatment with a neutralizing antibody against TGF1β impaired proliferation; subsequent introduction of recombinant TGF1β restored proliferation and induced the DP phenotype in PDAC cells. Analysis of PDAC patient tumor glands revealed a relationship between stromal content and PDAC cell type and identified 8 distinct gland types defined by their composition of DP, PRO, EMT, and double-negative cells and correlated with response to different therapies. These results demonstrate the importance of stromal CAFs in influencing PDAC tumor composition, signaling, biology, and response to therapy.

Ligorio M, Sil S, Malagon-Lopez J, Nieman LT, Misale S, Di Pilato M, et al. Stromal microenvironment shapes the intratumoral architecture of pancreatic cancer. Cell 2019;178:160–75.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.