Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
Department of Anatomical Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
Cancer Cell. 2021 Apr 12;39(4):548-565.e6. doi: 10.1016/j.ccell.2021.02.007. Epub 2021 Mar 4.
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.
胰腺导管腺癌 (PDAC) 中的基质促结缔组织增生反应涉及 I 型胶原 (Col1) 的大量积累。然而，Col1 在 PDAC 进展中的精确分子和机制贡献仍不清楚。活化的胰腺星状细胞/αSMA 肌成纤维细胞是 PDAC 基质中 Col1 的主要贡献者。我们使用自发性 PDAC 的双重组酶基因小鼠模型，特异性地在肌成纤维细胞中删除 Col1。这导致总基质 Col1 含量的显著减少，并加速 PanINs 和 PDAC 的出现，降低整体存活率。Col1 的缺失导致癌细胞中 Sox9 上调 Cxcl5。Cxcl5 的增加与髓系来源的抑制细胞的募集和 CD8 T 细胞的抑制有关，通过联合靶向 CXCR2 和 CCR2 可以减轻这种抑制，从而抑制基质 Col1 缺失时加速的 PDAC 进展。我们的结果揭示了肌成纤维细胞衍生的 Col1 在调节肿瘤免疫和抑制 PDAC 进展中的基本作用。
