Related Experiment Video
Updated: Jul 23, 2025
Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
Multiple intratumoral sources of kit ligand promote gastrointestinal stromal tumor
Andrew D Tieniber1, Ferdinando Rossi1, Andrew N Hanna1
1Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
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.
Insights
Kit ligand (KitL) fuels gastrointestinal stromal tumor (GIST) growth, even after therapy. Targeting KitL may offer new therapeutic strategies for this common sarcoma.
Area of Science:
- Oncology
- Molecular Biology
- Sarcoma Research
Background:
- Gastrointestinal stromal tumor (GIST) is the most common human sarcoma, often driven by Kit or PDGFRA mutations.
- Tyrosine kinase inhibitors (TKIs) are effective but not curative for GIST.
- Kit ligand (KitL) is the natural ligand for the Kit receptor, existing in soluble and membrane-bound forms.
Purpose of the Study:
- Investigate intratumoral KitL sources in a mouse model of GIST with a common human KIT mutation.
- Determine the importance of KitL in GIST oncogenesis and its contribution to tumor growth in vivo.
- Evaluate KitL as a potential biomarker and therapeutic target in GIST.
Main Methods:
- Utilized a genetically engineered mouse model (KitV558Δ/+) of GIST.
- Employed genetic reduction of KitL in tumor cells.
- Analyzed GIST specimens using RNA sequencing, quantitative PCR, and immunohistochemistry.
- Measured serum KitL levels in GIST patients.
Main Results:
- KitL is produced by GIST cells, endothelia, and smooth muscle cells, persisting after imatinib therapy.
- Genetic reduction of KitL in tumor cells impaired GIST growth in vivo.
- Reduced soluble KitL in tumor cells decreased GIST size.
- PDGFRA-mutant GIST showed higher KitL expression than Kit-mutant GIST.
- Elevated serum KitL correlated with imatinib resistance and higher tumor KitL RNA levels.
Conclusions:
- KitL supports GIST growth at baseline and post-TKI therapy.
- Intratumoral KitL sources, including non-tumor cells, contribute to GIST progression.
- KitL represents a potential therapeutic target and predictive biomarker for GIST.
