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

Autor: Chakraborty S; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Bhat AM; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Mushtaq I; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; Incyte Corporation, Wilmington, DE, USA., Luan H; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Kalluchi A; Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Mirza S; Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; Department of Chemistry, College of Science, United Arab Emirates University, Al Ain, UAE., Storck MD; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Chaturvedi N; Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Lopez-Guerrero JA; Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain., Llombart-Bosch A; Department of Pathology, University of Valencia, Avd. Blasco Ibáñez 15, 46010, Valencia, Spain., Machado I; Department of Pathology, University of Valencia, Avd. Blasco Ibáñez 15, 46010, Valencia, Spain., Scotlandi K; Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy., Meza JL; Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Ghosal G; Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Coulter DW; Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Jordan Rowley M; Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Band V; Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Mohapatra BC; Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA. bmohapat@unmc.edu.; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA. bmohapat@unmc.edu., Band H; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA. hband@unmc.edu.; Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA. hband@unmc.edu.; Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE, 68198, USA. hband@unmc.edu.; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA. hband@unmc.edu.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2023 Jul 20; Vol. 6 (1), pp. 758. Date of Electronic Publication: 2023 Jul 20.
DOI: 10.1038/s42003-023-05125-1
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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