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

Author

Listed:
  • 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)
    Frederick National Laboratory for Cancer Research (FNLCR))

  • Karen Morris

    (National Cancer Institute (NCI)
    Frederick National Laboratory for Cancer Research (FNLCR))

  • 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
    Centessa Pharmaceuticals)

  • Xiaoyan M. Zhang

    (BioMed Valley Discoveries, Inc
    Ikena Oncology)

  • Enrique Zudaire

    (National Cancer Institute (NCI)
    Janssen Pharmaceutical Companies, J&J, R&D)

  • Pradip Bajgain

    (National Cancer Institute (NCI))

  • Joshua Rose

    (Center for Structural Biology, NCI, NIH)

  • Zhongyu Zhu

    (Cancer and Inflammation Program, NCI, NIH
    Lentigen Technology)

  • Dimiter S. Dimitrov

    (Cancer and Inflammation Program, NCI, NIH
    University of Pittsburgh School of Medicine)

  • Frank Cuttitta

    (National Cancer Institute (NCI))

  • Nancy J. Emenaker

    (NCI, NIH)

  • Lino Tessarollo

    (NCI, NIH)

  • Brad St. Croix

    (National Cancer Institute (NCI))

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.

Suggested Citation

  • 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, 2022. "Cancer cell survival depends on collagen uptake into tumor-associated stroma," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34643-5
    DOI: 10.1038/s41467-022-34643-5
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