Received: 18 March 2022
Accepted: 1 November 2022
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Kuo-Sheng Hsu1 , James M. Dunleavey1 , Christopher Szot1 , Liping Yang1, Mary Beth Hilton1,2, Karen Morris1,2, Steven Seaman 1, Yang Feng1, Emily M. Lutz1, Robert Koogle3, Francesco Tomassoni-Ardori3, Saurabh Saha4,9, Xiaoyan M. Zhang4,10, Enrique Zudaire1,11, Pradip Bajgain 1, Joshua Rose 5, Zhongyu Zhu6,12, Dimiter S. Dimitrov 6,13, Frank Cuttitta1 , Nancy J. Emenaker7, Lino Tessarollo 8 & Brad St. Croix 1
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.