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ResearchIn-Press PreviewAngiogenesisOncology Open Access | 10.1172/JCI181609

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

Yuyi Wang,1 Hidetaka Ohnuki,1 Andy D. Tran,2 Dunrui Wang,1 Taekyu Ha,1 Jing-Xin Feng,1 Minji Sim,1 Raymond Barnhill,3 Claire Lugassy,3 Michael R. Sargen,4 Emanuel Salazar-Cavazos,5 Michael Kruhlak,2 and Giovanna Tosato1

1Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

2Center for Cancer Research Microscopy Core, Laboratory of Cancer Biology an, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

3Department of Translational Research, Institut Curie, Paris, France

4Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, United States of America

5Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Institutes of Health, Bethesda, United States of America

Find articles by Wang, Y. in: JCI | PubMed | Google Scholar

1Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

2Center for Cancer Research Microscopy Core, Laboratory of Cancer Biology an, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

3Department of Translational Research, Institut Curie, Paris, France

4Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, United States of America

5Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Institutes of Health, Bethesda, United States of America

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1Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

2Center for Cancer Research Microscopy Core, Laboratory of Cancer Biology an, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

3Department of Translational Research, Institut Curie, Paris, France

4Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, United States of America

5Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Institutes of Health, Bethesda, United States of America

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1Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

2Center for Cancer Research Microscopy Core, Laboratory of Cancer Biology an, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

3Department of Translational Research, Institut Curie, Paris, France

4Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, United States of America

5Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Institutes of Health, Bethesda, United States of America

Find articles by Wang, D. in: JCI | PubMed | Google Scholar

1Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

2Center for Cancer Research Microscopy Core, Laboratory of Cancer Biology an, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

3Department of Translational Research, Institut Curie, Paris, France

4Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, United States of America

5Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Institutes of Health, Bethesda, United States of America

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1Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

2Center for Cancer Research Microscopy Core, Laboratory of Cancer Biology an, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

3Department of Translational Research, Institut Curie, Paris, France

4Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, United States of America

5Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Institutes of Health, Bethesda, United States of America

Find articles by Feng, J. in: JCI | PubMed | Google Scholar |

1Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

2Center for Cancer Research Microscopy Core, Laboratory of Cancer Biology an, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

3Department of Translational Research, Institut Curie, Paris, France

4Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, United States of America

5Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Institutes of Health, Bethesda, United States of America

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1Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

2Center for Cancer Research Microscopy Core, Laboratory of Cancer Biology an, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

3Department of Translational Research, Institut Curie, Paris, France

4Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, United States of America

5Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Institutes of Health, Bethesda, United States of America

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1Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

2Center for Cancer Research Microscopy Core, Laboratory of Cancer Biology an, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

3Department of Translational Research, Institut Curie, Paris, France

4Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, United States of America

5Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Institutes of Health, Bethesda, United States of America

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1Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

2Center for Cancer Research Microscopy Core, Laboratory of Cancer Biology an, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

3Department of Translational Research, Institut Curie, Paris, France

4Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, United States of America

5Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Institutes of Health, Bethesda, United States of America

Find articles by Sargen, M. in: JCI | PubMed | Google Scholar

1Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

2Center for Cancer Research Microscopy Core, Laboratory of Cancer Biology an, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

3Department of Translational Research, Institut Curie, Paris, France

4Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, United States of America

5Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Institutes of Health, Bethesda, United States of America

Find articles by Salazar-Cavazos, E. in: JCI | PubMed | Google Scholar

1Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

2Center for Cancer Research Microscopy Core, Laboratory of Cancer Biology an, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

3Department of Translational Research, Institut Curie, Paris, France

4Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, United States of America

5Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Institutes of Health, Bethesda, United States of America

Find articles by Kruhlak, M. in: JCI | PubMed | Google Scholar

1Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

2Center for Cancer Research Microscopy Core, Laboratory of Cancer Biology an, National Cancer Institute, National Institutes of Health, Bethesda, United States of America

3Department of Translational Research, Institut Curie, Paris, France

4Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, United States of America

5Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Institutes of Health, Bethesda, United States of America

Find articles by Tosato, G. in: JCI | PubMed | Google Scholar |

Published March 25, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI181609.
Copyright © 2025, Wang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 25, 2025 - Version history
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Abstract

Allosteric inhibitors of the tyrosine phosphatase 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 alters 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 display a typically subverted architecture where proliferative tumor cells cluster in distinct “vascular islands” centered by remodeled vessels, each limited by surrounding hypoxic and dead tumor tissue, where inflammatory blood cells are limited. Although vascular islands generally reflect protected sanctuaries for tumor cells, we found that vascular island-resident, highly proliferative, SHP2-depleted tumor cells acquire an increased sensitivity to blocking MEK/ERK signaling resulting in reduced tumor growth. Our results show that response to targeted therapies in resistant tumor cells is controlled by tumor cell-induced vascular changes and tumor architectural reorganization providing a compelling approach to eliciting tumor response by exploiting tumor and endothelial-dependent biochemical changes.

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