Myofibroblastic cancer‐associated fibroblast subtype heterogeneity in pancreatic cancer

• Published in: Journal of surgical oncology 2024-04, Vol.129 (5), p.860-868
• Main Authors: Kearney, Joseph F., Trembath, Hannah E., Chan, Priscilla S., Morrison, Ashley B., Xu, Yi, Luan, Chang Fei, McCabe, Ian C., Zarmer, Sandra A., Kim, Hong Jin, Peng, Xianlu L., Yeh, Jen Jen
• Format: Article
• Language: English
• Subjects: Cancer; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; cancer‐associated fibroblasts; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Fibroblasts; Fibroblasts - metabolism; Gene expression; Humans; pancreatic adenocarcinoma; Pancreatic cancer; Pancreatic Neoplasms - pathology; Protein expression; Proteins; Tumor Microenvironment
• ISSN: 0022-4790; 1096-9098; 1096-9098
• DOI: 10.1002/jso.27582

Background Pancreatic ductal adenocarcinoma (PDAC) has a fibrotic stroma that has both tumor‐promoting and tumor‐restraining properties. Different types of cancer‐associated fibroblasts (CAFs) have been described. Here, we investigated whether CAFs within the same subtype exhibit heterogeneous functions. Methods We evaluated the gene and protein expression differences in two myofibroblastic CAF (myCAF) lines using single‐cell and bulk RNA‐sequencing. We utilized proliferation and migration assays to determine the effect of different CAF lines on a tumor cell line. Results We found that myCAF lines express an activated stroma subtype gene signature, which is associated with a shorter survival in patients. Although both myCAF lines expressed α‐smooth muscle actin (α‐SMA), platelet‐derived growth factor‐α (PDGFR‐α), fibroblast‐activated protein (FAP), and vimentin, we observed heterogeneity between the two lines. Similarly, despite being consistent with myCAF gene expression overall, heterogeneity within specific genes was observed. We found that these differences extended to the functional level where the two myCAF lines had different effects on the same tumor cell line. The myCAF216 line, which had slightly increased inflammatory CAF‐like gene expression and higher protein expression of α‐SMA, PDGFR‐α, and FAP was found to restrain migration of tumor cells. Conclusions We found that two myCAF lines with globally similar expression characteristics had different effects on the same tumor cell line, one promoting and the other restraining migration. Our study highlights that there may be unappreciated heterogeneity within CAF subtypes. Further investigation and attention to specific genes or proteins that may drive this heterogeneity will be important.