Chen et al. investigated the role of type I collagen (Col1) in pancreatic ductal carcinoma (PDAC) by specifically deleting Col1 in αSMA+ myofibroblasts. Using a spontaneous dual-recombinase PDAC model, reduction of total stromal Col1 resulted in accelerated PDAC growth and decreased overall survival. Col1 deletion resulted in increased tumor Cxcl5 expression via SOX9, leading to recruitment of F4/80+Arg1+ MDSCs and decreased numbers of activated CD8+ T cells. Combined inhibition of CXCR2 (receptor for CXCL5) and CCR2 (monocyte chemoattractant protein-1) reversed the tumor progression induced by loss of myofibroblast Col1.
Contributed by Katherine Turner
ABSTRACT: Stromal desmoplastic reaction in pancreatic ductal adenocarcinoma (PDAC) involves significant accumulation of type I collagen (Col1). However, the precise molecular and mechanistic contribution of Col1 in PDAC progression remains unknown. Activated pancreatic stellate cells/αSMA+ myofibroblasts are major contributors of Col1 in the PDAC stroma. We use a dual-recombinase genetic mouse model of spontaneous PDAC to delete Col1 specifically in myofibroblasts. This results in significant reduction of total stromal Col1 content and accelerates the emergence of PanINs and PDAC, decreasing overall survival. Col1 deletion leads to Cxcl5 upregulation in cancer cells via SOX9. Increase in Cxcl5 is associated with recruitment of myeloid-derived suppressor cells and suppression of CD8+ T cells, which can be attenuated with combined targeting of CXCR2 and CCR2 to restrain accelerated PDAC progression in the setting of stromal Col1 deletion. Our results unravel the fundamental role of myofibroblast-derived Co1l in regulating tumor immunity and restraining PDAC progression.
Author Info: (1) Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. (2) Department of Cancer Biology, University of Texas MD Anderson Cancer Ce
Author Info: (1) Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. (2) Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. (3) Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. (4) Department of Anatomical Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. (5) Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. (6) Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. (7) Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. (8) Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address: rkalluri@mdanderson.org.
