Haploinsufficiency of the ESCRT Component HD-PTP Predisposes to Cancer

• DOI: 10.1016/j.celrep.2016.04.076
• Publication Date: 2016-05-21T05:01:20Z
• Authors: Sanaz Manteghi; Marie-Claude Gingras; Dmitri Kharitidi; Luc Galarneau; Maud Marques; Ming Yan; Regina Cencic; Francis Robert; Marilène Paquet; Michael Witcher; Jerry Pelletier; Arnim Pause
• Keywords: Hemizygote; 0301 basic medicine; Integrins; Endosomal Sorting Complexes Required for Transport; QH301-705.5; Carcinogenesis; Cell Survival; Haploinsufficiency; Protein Tyrosine Phosphatases, Non-Receptor; 3. Good health; Mice, Inbred C57BL; Proto-Oncogene Proteins c-myc; 03 medical and health sciences; Cell Movement; Neoplasms; Animals; Humans; Genetic Predisposition to Disease; Neoplasm Invasiveness; Biology (General)

Endosomal sorting complexes required for transport (ESCRT) drive cell surface receptor degradation resulting in attenuation of oncogenic signaling and pointing to a tumor suppressor function. Here, we show that loss of function of an ESCRT protein (HD-PTP encoded by the PTPN23 gene, located on the tumor suppressor gene cluster 3p21.3) drives tumorigenesis in vivo. Indeed, Ptpn23(+/-) loss predisposes mice to sporadic lung adenoma, B cell lymphoma, and promotes Myc-driven lymphoma onset, dissemination, and aggressiveness. Ptpn23(+/-)-derived tumors exhibit an unaltered remaining allele and maintain 50% of HD-PTP expression. Consistent with the role of HD-PTP in attenuation of integrin recycling, cell migration, and invasion, hemizygous Ptpn23(+/-) loss increases integrin β1-dependent B cell lymphoma survival and dissemination. Finally, we reveal frequent PTPN23 deletion and downregulation in human tumors that correlates with poor survival. Altogether, we establish HD-PTP/PTPN23 as a prominent haploinsufficient tumor suppressor gene preventing tumor progression through control of integrin trafficking.