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

Sukanya Chakraborty, Aaqib M. Bhat, Insha Mushtaq, Haitao Luan, Achyuth Kalluchi, Sameer Mirza, Matthew D. Storck, Nagendra Chaturvedi, Jose Antonio Lopez-Guerrero, Antonio Llombart-Bosch, Isidro Machado, Katia Scotlandi, Jane L. Meza, Gargi Ghosal, Donald W. Coulter, M. Jordan Rowley, Vimla Band, Bhopal C. Mohapatra, Hamid Band

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Overexpression of the EPS15 Homology Domain containing 1 (EHD1) protein 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 EHD1 mRNA expression specifying shorter patient survival. ShRNA-knockdown and CRISPR-knockout with mouse Ehd1 rescue established a requirement of EHD1 for tumorigenesis and metastasis. RTK antibody arrays identified 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.

Original languageEnglish (US)
Article number758
JournalCommunications biology
Volume6
Issue number1
DOIs
StatePublished - Dec 2023

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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