EHD1-dependent traffic of IGF-1 receptor to the cell surface is essential for Ewing sarcoma tumorigenesis and metastasis

Chakraborty, S.; Bhat, A. M.; Mushtaq, I.; Luan, H.; Kalluchi, A.; Mirza, S.; Storck, M. D.; Chaturvedi, N.; Lopez-Guerrero, J. A.; Llombart-Bosch, A.; Machado, I.; Meza, J. L.; Ghosal, G.; Coulter, D. W.; Rowley, J. M.; Band, V.; Mohapatra, B. C.; Band, H.

doi:10.1101/2023.01.15.524130

bioRxiv · 10.1101/2023.01.15.524130

EHD1-dependent traffic of IGF-1 receptor to the cell surface is essential for Ewing sarcoma tumorigenesis and metastasis

Chakraborty, S.·Bhat, A. M.·Mushtaq, I.·Luan, H.·Kalluchi, A.·Mirza, S.·Storck, M. D.·Chaturvedi, N.·Lopez-Guerrero, J. A.·Llombart-Bosch, A.·Machado, I.·Meza, J. L.·Ghosal, G.·Coulter, D. W.·Rowley, J. M.·Band, V.·Mohapatra, B. C.·Band, H.

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Abstract

Overexpression of EPS15 Homology Domain containing 1 (EHD1) has been linked to tumorigenesis but whether its core function as a regulator of intracellular traffic of cell surface receptors plays a role in oncogenesis remains unknown. We establish that EHD1 is overexpressed in Ewing sarcoma (EWS), with high EHD mRNA expression specifying shorter patient survival. ShRNA and CRISPR-knockout with mouse Ehd1 rescue established a requirement of EHD1 for tumorigenesis and metastasis. RTK antibody arrays identified the IGF-1R as a target of EHD1 regulation in EWS. Mechanistically, we demonstrate a requirement of EHD1 for endocytic recycling and Golgi to plasma membrane traffic of IGF-1R to maintain its surface expression and downstream signaling. Conversely, EHD1 overexpression-dependent exaggerated oncogenic traits require IGF-1R expression and kinase activity. Our findings define the RTK traffic regulation as a proximal mechanism of EHD1 overexpression-dependent oncogenesis that impinges on IGF-1R in EWS, supporting the potential of IGF-1R and EHD1 co-targeting.

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Chakraborty, S., Bhat, A. M., Mushtaq, I., Luan, H., Kalluchi, A., Mirza, S., Storck, M. D., Chaturvedi, N., Lopez-Guerrero, J. A., Llombart-Bosch, A., Machado, I., Meza, J. L., Ghosal, G., Coulter, D. W., Rowley, J. M., Band, V., Mohapatra, B. C., Band, H.. 2023-01-18. EHD1-dependent traffic of IGF-1 receptor to the cell surface is essential for Ewing sarcoma tumorigenesis and metastasis. https://doi.org/10.1101/2023.01.15.524130

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