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Multiple intratumoral sources of kit ligand promote gastrointestinal stromal tumor.

Andrew D TieniberFerdinando RossiAndrew N HannaMarion LiuMark S EtheringtonJennifer K LooNesteene ParamShan ZengKevin DoLaura WangRonald P DeMatteo
Published in: Oncogene (2023)
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 Kit V558Δ/+ tumors, even after imatinib therapy. Genetic reduction of total KitL in tumor cells of Kit V558Δ/+ mice impaired tumor growth in vivo. Similarly, genetic reduction of tumor cell soluble KitL in Kit V558Δ/+ 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.
Keyphrases
  • endothelial cells
  • mouse model
  • induced pluripotent stem cells
  • pluripotent stem cells
  • single cell
  • genome wide
  • drinking water
  • rectal cancer
  • long non coding rna
  • mesenchymal stem cells
  • cell therapy