In contrast to normal type I collagen (Col1) heterotrimer (α1/α2/α1) produced by fibroblasts, pancreatic cancer cells specifically produce unique Col1 homotrimer (α1/α1/α1). Col1 homotrimer results from epigenetic suppression of the Col1a2 gene and promotes oncogenic signaling, cancer cell proliferation, tumor organoid formation, and growth via α3β1 integrin on cancer cells, associated with tumor microbiome enriched in anaerobic Bacteroidales in hypoxic and immunosuppressive tumors. Deletion of Col1 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-α3β1 integrin signaling axis as a cancer-specific therapeutic target.

与成纤维细胞产生的正常 I 型胶原 (Col1) 异三聚体 (α1/α2/α1) 不同，胰腺癌细胞特异性产生独特的 Col1 同三聚体 (α1/α1/α1)。Col1 同源三聚体源自Col1a2基因的表观遗传抑制，并通过癌细胞上的 α3β1 整合素促进致癌信号传导、癌细胞增殖、肿瘤类器官形成和生长，与缺氧和免疫抑制肿瘤中富含厌氧拟杆菌的肿瘤微生物组相关。Col1 同源三聚体的缺失可增加胰腺导管腺癌 (PDAC) 小鼠的总体存活率，这与微需氧弯曲杆菌增加导致的肿瘤微生物组重新编程有关，而广谱抗生素可以逆转这种情况。Col1 同源三聚体的缺失可增强 T 细胞浸润并实现抗 PD-1 免疫疗法的功效。这项研究确定了 Col1 同源三聚体对肿瘤微生物组和肿瘤免疫的功能影响，表明 Col1 同源三聚体-α3β1 整合素信号轴作为癌症特异性治疗靶点。