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Induced clustering of SHP2-depleted tumor cells in vascular islands restores sensitivity to MEK/ERK inhibition
Yuyi Wang, … , Michael Kruhlak, Giovanna Tosato
Yuyi Wang, … , Michael Kruhlak, Giovanna Tosato
Published March 25, 2025
Citation Information: J Clin Invest. 2025;135(10):e181609. https://doi.org/10.1172/JCI181609.
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Research Article Angiogenesis Oncology

Induced clustering of SHP2-depleted tumor cells in vascular islands restores sensitivity to MEK/ERK inhibition

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Abstract

Allosteric inhibitors of the tyrosine phosphatase Src homology 2 domain–containing protein tyrosine phosphatase 2 (SHP2) hold therapeutic promise in cancers with overactive RAS/ERK signaling, but adaptive resistance to SHP2 inhibitors may limit benefits. Here, we utilized tumor cells that proliferate similarly with or without endogenous SHP2 to explore means to overcome this growth independence from SHP2. We found that SHP2 depletion profoundly altered the output of vascular regulators, cytokines, chemokines, and other factors from SHP2 growth-resistant cancer cells. Tumors derived from inoculation of SHP2-depleted, but SHP2 growth–independent, mouse melanoma and colon carcinoma cell lines displayed a typically subverted architecture, in which proliferative tumor cells surrounding a remodeled vessel formed “vascular islands”, each limited by surrounding hypoxic and dead tumor tissue, where inflammatory blood cells were limited. Although vascular islands generally reflect protected sanctuaries for tumor cells, we found that vascular island–resident, highly proliferative, SHP2-depleted tumor cells acquired an increased sensitivity to blockage of MEK/ERK signaling, resulting in reduced tumor growth. Our results show that the response to targeted therapies in resistant tumor cells was controlled by tumor cell–induced vascular changes and tumor architectural reorganization, providing a compelling approach to elicit tumor responses by exploiting tumor- and endothelium-dependent biochemical changes.

Authors

Yuyi Wang, Hidetaka Ohnuki, Andy D. Tran, Dunrui Wang, Taekyu Ha, Jing-Xin Feng, Minji Sim, Raymond Barnhill, Claire Lugassy, Michael R. Sargen, Emanuel Salazar-Cavazos, Michael Kruhlak, Giovanna Tosato

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