Identification of Functional Heterogeneity of Carcinoma-Associated Fibroblasts with Distinct IL6-Mediated Therapy Resistance in Pancreatic Cancer

Abstract The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of fibroblasts as part of the host response to cancer. Using single-cell RNA sequencing, multiplex immunostaining, and several genetic mouse models, we identify carcinoma-associated fibroblasts (CAF) with opposing functions in PDAC progression. Depletion of fibroblast activation protein (FAP)+ CAFs results in increased survival, in contrast to depletion of alpha smooth muscle actin (αSMA)+ CAFs, which leads to decreased survival. Tumor-promoting FAP+ CAFs (TP-CAF) and tumor-restraining αSMA+ CAFs (TR-CAF) differentially regulate cancer-associated pathways and accumulation of regulatory T cells.…

• SW
  Sid W. Richardson Foundation
• CP
  Cancer Prevention and Research Institute of Texas

  Awards: P30CA016672, UL1TR000371, RP150231
• NI
  National Institutes of Health

  Awards: P30CA016672, P01CA117969, UL1TR000371, NIH P30CA016672
• UO
  University of Texas MD Anderson Cancer Center

  Awards: P30CA016672, NIH P30CA016672
• CF
  Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston

  Award: UL1TR000371
• NC
  National Cancer Institute

  Awards: P01CA117969, UL1TR000371, P30CA016672