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

Kuo-Sheng Hsu, James M. Dunleavey, Christopher Szot, Liping Yang, Mary Beth Hilton, Karen Morris, Steven Seaman, Yang Feng, Emily M. Lutz, Robert Koogle, Francesco Tomassoni-Ardori, Saurabh Saha, Xiaoyan M. Zhang, Enrique Zudaire, Pradip Bajgain, Joshua Rose, Zhongyu Zhu, Dimiter S. Dimitrov, Frank Cuttitta, Nancy J. Emenaker, Lino Tessarollo and Brad St. Croix ()
Additional contact information
Kuo-Sheng Hsu: National Cancer Institute (NCI)
James M. Dunleavey: National Cancer Institute (NCI)
Christopher Szot: National Cancer Institute (NCI)
Liping Yang: National Cancer Institute (NCI)
Mary Beth Hilton: National Cancer Institute (NCI)
Karen Morris: National Cancer Institute (NCI)
Steven Seaman: National Cancer Institute (NCI)
Yang Feng: National Cancer Institute (NCI)
Emily M. Lutz: National Cancer Institute (NCI)
Robert Koogle: NCI
Francesco Tomassoni-Ardori: NCI
Saurabh Saha: BioMed Valley Discoveries, Inc
Xiaoyan M. Zhang: BioMed Valley Discoveries, Inc
Enrique Zudaire: National Cancer Institute (NCI)
Pradip Bajgain: National Cancer Institute (NCI)
Joshua Rose: Center for Structural Biology, NCI, NIH
Zhongyu Zhu: Cancer and Inflammation Program, NCI, NIH
Dimiter S. Dimitrov: Cancer and Inflammation Program, NCI, NIH
Frank Cuttitta: National Cancer Institute (NCI)
Nancy J. Emenaker: NCI, NIH
Lino Tessarollo: NCI, NIH
Brad St. Croix: National Cancer Institute (NCI)

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34643-5

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