Abstract
Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and is typically driven by a single mutation in the Kit or PDGFRA receptor. While highly effective, tyrosine kinase inhibitors (TKIs) are not curative. The natural ligand for the Kit receptor is Kit ligand (KitL), which exists in both soluble and membrane-bound forms. While KitL is known to stimulate human GIST cell lines in vitro, we used a genetically engineered mouse model of GIST containing a common human KIT mutation to investigate the intratumoral sources of KitL, importance of KitL during GIST oncogenesis, and contribution of soluble KitL to tumor growth in vivo. We discovered that in addition to tumor cells, endothelia and smooth muscle cells produced KitL in KitV558Δ/+ tumors, even after imatinib therapy. Genetic reduction of total KitL in tumor cells of KitV558Δ/+ mice impaired tumor growth in vivo. Similarly, genetic reduction of tumor cell soluble KitL in KitV558Δ/+ mice decreased tumor size. By RNA sequencing, quantitative PCR, and immunohistochemistry, KitL expression was heterogeneous in human GIST specimens. In particular, PDGFRA-mutant tumors had much higher KitL expression than Kit-mutant tumors, suggesting the benefit of Kit activation in the absence of mutant KIT. Serum KitL was higher in GIST patients with tumors resistant to imatinib and in those with tumors expressing more KitL RNA. Overall, KitL supports the growth of GIST at baseline and after imatinib therapy and remains a potential biomarker and therapeutic target.
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Data availability
ScRNAseq data presented in this work are submitted through the Sequencing Read Archive under the accession number PRJNA945239. The remaining data generated and/or analyzed during the current study are available within the article and its Supplementary Data files or are available from the corresponding author upon reasonable request.
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Funding
The investigators were supported by NIH grants R01 CA102613 and T32 CA251063 (RPD).
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ADT: Conceptualization, data curation, formal analysis, validation, investigation, methodology, writing–original draft, writing—review and editing. FR: Conceptualization, data curation, formal analysis, validation, investigation, methodology, writing–original draft, writing–review and editing. ANH: Conceptualization, data curation, formal analysis, validation, writing–review and editing. ML: Conceptualization, Data curation, formal analysis. MSE: Data curation, formal analysis. JKL: Data curation, formal analysis. N. Param: Data curation, formal analysis. SZ: Data curation, formal analysis. KJD: Data curation, validation. LW: Data curation, validation. RPD: Conceptualization, resources, supervision, funding acquisition, writing–original draft, project administration, writing–review and editing.
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Tieniber, A.D., Rossi, F., Hanna, A.N. et al. Multiple intratumoral sources of kit ligand promote gastrointestinal stromal tumor. Oncogene 42, 2578–2588 (2023). https://doi.org/10.1038/s41388-023-02777-5
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DOI: https://doi.org/10.1038/s41388-023-02777-5