Oncogenic Collagen I Homotrimers From Cancer Cells Bind to α3β1 Integrin and Impact Tumor Microbiome and Immunity To Promote Pancreatic Cancer

Authors

Yang Chen
Sujuan Yang
Jena Tavormina
Desiree Tampe
Michael Zeisberg
Huamin Wang
Krishnan K Mahadevan
Chang-Jiun Wu
Hikaru Sugimoto
Chia-Chi Chang
Robert R Jenq
Kathleen M McAndrews
Raghu Kalluri

Publication Date

8-8-2022

Journal

Cancer Cell

Abstract

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.

Keywords

Animals, Carcinogenesis, Carcinoma, Pancreatic Ductal, Collagen, Collagen Type I, Integrin alpha3beta1, Mice, Microbiota, Pancreatic Neoplasms

DOI

10.1016/j.ccell.2022.06.011

PMID

35868307

PMCID

PMC9831277

PubMedCentral® Posted Date

8-8-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes