Cancer-associated fibroblast secretion of PDGFC promotes gastrointestinal stromal tumor growth and metastasis

Hyunho Yoon, Chih Min Tang, Sudeep Banerjee, Mayra Yebra, Sangkyu Noh, Adam M. Burgoyne, Jorge De la Torre, Martina De Siena, Mengyuan Liu, Lillian R. Klug, Yoon Young Choi, Mojgan Hosseini, Antonio L. Delgado, Zhiyong Wang, Randall P. French, Andrew Lowy, Ronald P. DeMatteo, Michael C. Heinrich, Alfredo A. Molinolo, J. Silvio GutkindOlivier Harismendy, Jason K. Sicklick

    Research output: Contribution to journalArticlepeer-review

    2 Scopus citations

    Abstract

    Targeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates.

    Original languageEnglish (US)
    Pages (from-to)1957-1973
    Number of pages17
    JournalOncogene
    Volume40
    Issue number11
    DOIs
    StatePublished - Mar 18 2021

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Cancer Research

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