Cancer cell survival depends on collagen uptake into tumor-associated stroma

• Published in: Nature communications Vol. 13; no. 1; p. 7078
• Main Authors: Hsu, Kuo-Sheng, Dunleavey, James M, Szot, Christopher, Yang, Liping, Hilton, Mary Beth, Morris, Karen, Seaman, Steven, Feng, Yang, Lutz, Emily M, Koogle, Robert, Tomassoni-Ardori, Francesco, Saha, Saurabh, Zhang, Xiaoyan M, Zudaire, Enrique, Bajgain, Pradip, Rose, Joshua, Zhu, Zhongyu, Dimitrov, Dimiter S, Cuttitta, Frank, Emenaker, Nancy J, Tessarollo, Lino, St Croix, Brad
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 18.11.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Alternative energy sources; Animal models; Animals; Antibodies; Binding; Cancer; Cell surface; Cell Survival; Collagen; Collagen (type I); Collagen - metabolism; Genetic engineering; Glutamine; Humans; Immunoconjugates; Metabolism; Mice; Microfilament Proteins; Neoplasms; Proteins; Receptors, Cell Surface; Solid tumors; Starvation; Stromal cells; Survival; Tumor cells; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34643-5

Collagen I, the most abundant protein in humans, is ubiquitous in solid tumors where it provides a rich source of exploitable metabolic fuel for cancer cells. While tumor cells were unable to exploit collagen directly, here we show they can usurp metabolic byproducts of collagen-consuming tumor-associated stroma. Using genetically engineered mouse models, we discovered that solid tumor growth depends upon collagen binding and uptake mediated by the TEM8/ANTXR1 cell surface protein in tumor-associated stroma. Tumor-associated stromal cells processed collagen into glutamine, which was then released and internalized by cancer cells. Under chronic nutrient starvation, a condition driven by the high metabolic demand of tumors, cancer cells exploited glutamine to survive, an effect that could be reversed by blocking collagen uptake with TEM8 neutralizing antibodies. These studies reveal that cancer cells exploit collagen-consuming stromal cells for survival, exposing an important vulnerability across solid tumors with implications for developing improved anticancer therapy.