Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell biological studies show that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)-dependent vesicular release from the Golgi. PI4KIIIβ-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIβ antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIβ-dependent secretion for cancer cell survival and tumor progression.
|Journal||Science Translational Medicine|
|State||Published - Jan 22 2020|
Bibliographical noteFunding Information:
This work was supported by the NIH through R01 CA181184 (to J.M.K.), R01 CA2111125 (to J.M.K.), R01AI099245 (to J.S.G.), U19AI109662 (to J.S.G.), P30 CA125123 (to C.J.C.), K99 CA225633 (to H.-F.G.), NIH Lung Cancer SPORE grant P50 CA70907 (to J.M.K. and I.I.W.), Lung Cancer Research Foundation FP#00005299 (to X.T.), and Department of Defense PROSPECT grant W81XWH-07-1-0306 (to I.I.W.). NCI P30 CA16672 Core grant supported flow cytometry. This work was funded by CPRIT-MIRA RP160652. J.M.K. holds the Elza A. and Ina S. Freeman Endowed Professorship in Lung Cancer. D.H.P. was supported by a CPRIT Graduate Scholar Training Grant (RP140106). D.L.G. is an R. Lee Clark Fellow of the University of Texas MD Anderson Cancer Center, supported by the Jeanne F Shelby Scholarship Fund. The work was also supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program. E.A.P. is supported by the Stanford ChEM-H Physician Scientist Research Fellowship.
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
ASJC Scopus subject areas
- Medicine (all)