Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
Department of Nephrology and Rheumatology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany.
Cancer Cell. 2022 Aug 8;40(8):818-834.e9. doi: 10.1016/j.ccell.2022.06.011. Epub 2022 Jul 21.
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)三聚体(α1/α2/α1)不同,胰腺癌细胞特异性产生独特的 Col1 三聚体(α1/α1/α1)。Col1 三聚体是由于 Col1a2 基因的表观遗传抑制而产生的,通过癌细胞上的α3β1 整合素促进致癌信号、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 三聚体的缺失增加了胰腺导管腺癌(PDAC)小鼠的总生存率,与肿瘤微生物组的重编程有关,即增加了微需氧弯曲杆菌,广谱抗生素可逆转这种情况。Col1 三聚体的缺失增强了 T 细胞浸润,并使抗 PD-1 免疫疗法有效。这项研究确定了 Col1 三聚体对肿瘤微生物组和肿瘤免疫的功能影响,暗示 Col1 三聚体-α3β1 整合素信号轴是一种癌症特异性治疗靶点。