Abstract
Cancer cell–derived Col1 homotrimers regulate the PDAC microbiome and block T-cell infiltration.
Major Finding: Cancer cell–derived Col1 homotrimers regulate the PDAC microbiome and block T-cell infiltration.
Concept: Col1 homotrimers promote PDAC progression by stimulating integrin α3β1–mediated oncogenic signaling.
Impact: Targeting oncogenic Col1 homotrimers renders PDAC sensitive to immune checkpoint blockade therapy.
A distinctive characteristic of pancreatic ductal adenocarcinoma (PDAC) is its fibrotic stroma that can make up as much as 80% of tumor volume. Type I collagen (Col1) is abundant in PDAC stroma and is produced by both myofibroblasts and tumor cells. Little is known, however, about the structure and function of Col1 produced by cancer cells (cancer-Col1) and how it differs from fibroblast-derived Col1. To describe the role of cancer-Col1 in the initiation and progression of PDAC, Chen and colleagues used both human cell lines and newly generated genetically engineered mouse models of PDAC cell–specific Col1 deletion and showed that cancer-Col1 has a distinct homotrimer structure (α1/α1/α1) rather than a standard heterotrimer (α1/α2/α1) Col1 molecule due to PDAC cells exclusively expressing COL1A1 as the α2 subunit COL1A2 is not expressed due to promoter hypermethylation. Deletion of Col1 in tumor cells demonstrated a morphologic shift as well as a decrease in proliferation, and reintroduction of supplemental Col1 homotrimers to culture conditions reversed these phenotypes. Similar results were observed in a murine model of PDAC in which tumor cell–specific Col1 knockout reduced tumor progression and increased survival. Mechanistically, cancer-Col1 was found to promote oncogenic signaling through interactions with the α3 subunit of integrin β1 (ITGA3), and, using the iExosome murine therapeutic system, ITGA3 knockdown led to increased T-cell infiltration and prolonged survival. Col1 deletion also altered both the intratumoral microbiome and the immune landscape as Col1-negative tumors recruited a protective microbiome and were depleted of myeloid-derived suppressor cells and were enriched for T cells. Interestingly, Col1 knockout alongside treatment with broad-spectrum antibiotics shortened survival and prevented immune cell composition changes, suggesting the microbiome itself influences immune cell composition. Finally, deletion of cancer-Col1 rendered PDAC tumors responsive to anti–PD-1 therapy. In summary, this study defined the functional role of cancer-Col1 and identified the Col1–integrin α3β1 signaling axis as a potential cancer-specific therapeutic target.
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.
RSS Feeds