TY - JOUR
T1 - EHD1-dependent traffic of IGF-1 receptor to the cell surface is essential for Ewing sarcoma tumorigenesis and metastasis
AU - Chakraborty, Sukanya
AU - Bhat, Aaqib M.
AU - Mushtaq, Insha
AU - Luan, Haitao
AU - Kalluchi, Achyuth
AU - Mirza, Sameer
AU - Storck, Matthew D.
AU - Chaturvedi, Nagendra
AU - Lopez-Guerrero, Jose Antonio
AU - Llombart-Bosch, Antonio
AU - Machado, Isidro
AU - Scotlandi, Katia
AU - Meza, Jane L.
AU - Ghosal, Gargi
AU - Coulter, Donald W.
AU - Jordan Rowley, M.
AU - Band, Vimla
AU - Mohapatra, Bhopal C.
AU - Band, Hamid
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s42003-023-05125-1
DO - 10.1038/s42003-023-05125-1
M3 - Article
C2 - 37474760
AN - SCOPUS:85165388348
SN - 2399-3642
VL - 6
JO - Communications biology
JF - Communications biology
IS - 1
M1 - 758
ER -