![]() 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. 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). Yet the molecular underpinnings and therapeutic implications of this feature remain unclear. Heightened secretion of pro-tumorigenic effector proteins is a feature of malignant cells. PI4KIIIβ-dependent secretion regulates processes in the tumor microenvironment. PLOD3 maintains H2122 cell survival by activating MMP9.įig. 1q amplification is associated with heightened secretion.įig. GOLPH3 mediates PI4KIIIβ-driven secretion.įig. GOLPH3 mediates pro-metastatic effects of PI4KIIIβ in 1q-amplified cancer cells.įig. PI4KIIIβ-dependent PI4P synthesis drives pro-metastatic properties of 1q-amplified lung cancer cells.įig. Selective PI4KIIIβ antagonists have activity against 1q-amplified lung cancer cells.įig. IN-9 induces apoptosis in 1q-amplified, but not 1q-diploid, lung cancer cells.įig. ![]() PI4KB functions cooperatively with co-amplified genes on chromosome 1q.įig. ![]() 1q-amplified cancers are PI4KIIIβ-dependent.įig. High expression of Golgi-related genes enhances the metastatic properties of 1q-amplified lung cancer cells.įig. Chromosome 1q is amplified in a subset of human lung cancer cell lines.įig. conceived and supervised the project and contributed to the design and interpretation of all experiments. directed and interpreted bioinformatic analyses. directed and interpreted mass spectrometry experiments. designed in vivo experiments with the antagonists and, along with K.N., directed and assisted with interpretation of data from those experiments. Compounds were characterized by F.U.N.R., K.N, G.L., and K.B. provided PI4KIIIβ antagonists, synthesized in his lab in collaboration with K.S., I.C., and M.S. optimized conditions for the invasion screen and provided ORFs for 1q-encoded genes. performed flow cytometric analysis of immune cells in tumor tissues and splenocyte co-culture assays. supervised the efforts of D.Y.D, L.M.S., B.M., M.G.R., and C.B. provided clinical annotation of the human tumor specimens. performed immunohistochemical analysis of murine tumor tissues. interpreted histologic findings in the autologous tumor model. ![]() optimized and carried out digital droplet PCR assays on tumor genomic DNA samples. performed the HUVEC tube formation assay. with analysis of confocal microscopic images. tested PI4KIIIβ antagonists in cell culture. bred and genotyped mice for the development of the autologous tumor model. performed invasion assay screens of 1q-encoded genes. assessed the anti-neoplastic properties of PI4KIIIβ antagonists in cell culture and edited the manuscript. conceived, designed, executed, and interpreted all of the confocal microscopy experiments to analyze Golgi-PI4P, TGN exit, and vesicular trafficking. conceived, designed, executed, and interpreted cell culture and in vivo experiments.
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