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

Published on Feb 18, 2021in Oncogene7.971
· DOI :10.1038/S41388-021-01685-W
Hyunho Yoon3
Estimated H-index: 3
(UCSD: University of California, San Diego),
Chih-Min Tang7
Estimated H-index: 7
(UCSD: University of California, San Diego)
+ 19 AuthorsJason K. Sicklick33
Estimated H-index: 33
(UCSD: University of California, San Diego)
Sources
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.
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References43
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#1Susanne Grunewald (University of Duisburg-Essen)H-Index: 7
#2Lillian R. Klug (OHSU: Oregon Health & Science University)H-Index: 6
Last. Sebastian BauerH-Index: 55
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Gastrointestinal stromal tumors (GIST) harboring activating mutations of PDGFRA respond to imatinib with the notable exception of the most common mutation, D842V. Avapritinib is a novel, potent KIT/PDGFRA inhibitor with substantial clinical activity in patients with the D842V genotype. To date, only a minority of PDGFRA-mutant patients treated with avapritinib have developed secondary resistance. Tumor and plasma biopsies in 6 of 7 patients with PDGFRA primary mutations who progressed on avaprit...
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#1Filip Janku (University of Texas MD Anderson Cancer Center)H-Index: 63
#2Albiruni Ryan Abdul Razak (Princess Margaret Cancer Centre)H-Index: 35
Last. Suzanne George (Harvard University)H-Index: 63
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PURPOSEIn advanced gastrointestinal stromal tumor (GIST), there is an unmet need for therapies that target both primary and secondary mutations of pathogenic KIT/PDGFRA oncoproteins. Ripretinib is ...
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#1Michael Heinrich (OHSU: Oregon Health & Science University)H-Index: 131
#2Robin L. Jones (The Royal Marsden NHS Foundation Trust)H-Index: 62
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Summary Background Targeting of KIT and PDGFRA with imatinib revolutionised treatment in gastrointestinal stromal tumour; however, PDGFRA Asp842Val (D842V)-mutated gastrointestinal stromal tumour is highly resistant to tyrosine kinase inhibitors. We aimed to assess the safety, tolerability, and antitumour activity of avapritinib, a novel KIT and PDGFRA inhibitor that potently inhibits PDGFRA D842V, in patients with advanced gastrointestinal stromal tumours, including patients with KIT and PDGFRA...
37 CitationsSource
#1Sohita Dhillon (Springer Science+Business Media)H-Index: 22
Ripretinib (QINLOCK™) is a novel type II tyrosine switch control inhibitor being developed by Deciphera Pharmaceuticals for the treatment of KIT proto-oncogene receptor tyrosine kinase (KIT)-driven and/or platelet derived growth factor receptor A (PDGFRA)-driven cancers, including gastrointestinal stromal tumour (GIST). Ripretinib inhibits KIT and PDGFRA kinase, including wild-type, primary and secondary mutations, as well as other kinases, such as PDGFRB, TIE2, VEGFR2 and BRAF. In May 2020, ora...
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#1Sohita Dhillon (Springer Science+Business Media)H-Index: 22
Avapritinib (AYVAKIT™) is a potent and selective tyrosine kinase inhibitor of platelet-derived growth factor receptor alpha (PDGFRA) and KIT activation loop mutants. It is being developed by Blueprint Medicines for the treatment of gastrointestinal stromal tumours (GIST), solid tumours and systemic mastocytosis. Avapritinib is approved in the USA for PDGFRA exon 18 (including D842V) mutant GIST and is undergoing regulatory assessment in the USA as a 4th-line treatment for GIST. Avapritinib is al...
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: Gastrointestinal stromal tumor (GIST) is the most common human sarcoma, frequently characterized by an oncogenic mutation in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes. We performed RNA sequencing of 75 human GIST tumors from 75 patients, comprising the largest cohort of GISTs sequenced to date, in order to discover differences in the immune infiltrates of KIT and PDGFRA-mutant GIST. Through bioinformatics, immunohistochemistry, and flow cytometry, we found that PD...
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This work was supported by the Deutsche Krebshilfe, Max Eder Research Group (110972) to AN. TEB, FMR, AG and DIJ were supported by Cancer Research UK (C14303/A17197) and the University of Cambridge. The Cancer Research UK CRUK Cambridge Institute also acknowledges its support from Hutchison Whampoa.
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Cancer-associated fibroblasts (CAFs) are the most abundant cells in the tumor microenvironment. Crosstalk between tumor cells and CAFs contributes to tumor survival in most epithelial cancers. Recently, utilizing gastrointestinal stromal tumor (GIST) as a model for sarcomas, we identified paracrine networks by which CAFs promote tumor progression and metastasis. However, the mechanisms by which CAFs arise in sarcomas remain unclear. Here, RNA sequencing analysis revealed that transforming growth...
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