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

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

doi:10.1038/s41388-021-01685-w

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.

Highlights

Gastrointestinal stromal tumor (GIST) is the most common sarcoma and is typically driven by oncogenic KIT or PDGFRA mutations [1,2,3]
PDGFRA and SLUG, implying that PDGFRA activation by platelet-derived growth factor C (PDGFC) in GIST is associated with SLUG expression (Supplementary Fig. 5i). These results suggest that cancer-associated fibroblasts (CAFs)-mediated induction of SLUG expression in GIST is driven by PDGFC ligand-dependent PDGFRA activation, and this correlates with tumor progression and metastasis
We provide the first evidence for the influence of CAFs on GIST progression and metastasis, and demonstrates that stromal/mesenchymal cancers may be highly dependent upon paracrine fibroblastic support, representing a paradigm shift for the field

Summary

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Gastrointestinal stromal tumor (GIST) is the most common sarcoma and is typically driven by oncogenic KIT or PDGFRA mutations [1,2,3] It subsequently reported that avapritinib-resistance occurs by tumors developing secondary PDGFRA mutations [18]. Despite their efficacies, no current single agent TKI therapy is sufficient for completely curing any GIST subtype. PDGFC-PDGFRA signal transduction promotes tumor growth and metastases via regulation of SLUG expression. Expression of this EMT transcription factor correlated with GIST size and mitotic index in metastatic tumors. Depleting CAFs was synergetic with imatinib therapy for treating GIST

Results

Discussion

Materials and methods

Compliance with ethical standards