Oncogenic collagen I homotrimers from cancer cells bind to α3β1 integrin and impact tumor microbiome and immunity to promote pancreatic cancer

In contrast to normal type I collagen (Col1) heterotrimer (alpha 1/alpha 2/alpha 1) produced by fibroblasts, pancreatic cancer cells specifically produce unique Col1 homotrimer (alpha 1/alpha 1/alpha 1). Coll homotrimer results from epigenetic suppression of the Col1a2 gene and promotes oncogenic signaling, cancer cell proliferation, tumor organoid formation, and growth via alpha 3 beta 1 integrin on cancer cells, associated with tumor microbiome enriched in anaerobic Bacteroidales in hypoxic and immunosuppressive tumors. Deletion of Coll homotrimers increases overall survival of mice with pancreatic ductal adenocarcinoma (PDAC), associated with reprograming of the tumor microbiome with increased microaerophilic Campylobacterales, which can be reversed with broad-spectrum antibiotics. Deletion of Col1 homotrimers enhances T cell infiltration and enables efficacy of anti-PD-1 immunotherapy. This study identifies the functional impact of Col1 homotrimers on tumor microbiome and tumor immunity, implicating Col1 homotrimer-alpha 3 beta 1 integrin signaling axis as a cancer-specific therapeutic target.