Overexpression of PRKCI, which occurs in the early stages of human ovarian cancer, was confirmed as an oncogenic driver in an inducible mouse model. PRKCI, via YAP1, activates TNFα expression and leads to infiltration by myeloid-derived suppressor cells, promoting an immunosuppressive tumor microenvironment and suppressing cytotoxic CD8+ T cell infiltration – observations consistent with analysis of human ovarian tumors.
A key feature of high-grade serous ovarian carcinoma (HGSOC) is frequent amplification of the 3q26 locus harboring PRKC-iota (PRKCI). Here, we show that PRKCI is also expressed in early fallopian tube lesions, called serous tubal intraepithelial carcinoma. Transgenic mouse studies establish PRKCI as an ovarian cancer-specific oncogene. Mechanistically, we show that the oncogenic activity of PRKCI relates in part to the up-regulation of TNFalpha to promote an immune-suppressive tumor microenvironment characterized by an abundance of myeloid-derived suppressor cells and inhibition of cytotoxic T-cell infiltration. Furthermore, system-level and functional analyses identify YAP1 as a downstream effector in tumor progression. In human ovarian cancers, high PRKCI expression also correlates with high expression of TNFalpha and YAP1 and low infiltration of cytotoxic T cells. The PRKCI-YAP1 regulation of the tumor immunity provides a therapeutic strategy for highly lethal ovarian cancer.
Author Info: (1) Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. (2) Department of Genomic Medicine, University of Texas M.D. Anderso
Author Info: (1) Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. (2) Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. Institute for Applied Cancer Science, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. (3) Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. (4) Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. (5) Division of Oncology, Clinical Research Institute at Rambam, Haifa 31096, Israel. (6) Department of Environmental Health, Boston University, Boston, Massachusetts 02118, USA. (7) Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. (8) Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. (9) Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. (10) Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. (11) Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. (12) KEW Group, Cambridge, Massachusetts 02139, USA. (13) Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. (14) Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. (15) Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. (16) Institute for Applied Cancer Science, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. (17) Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. Department of Dermatology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. (18) Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. Center for RNA Interference and Non-Coding RNA, University of Texas M.D. Anderson Cancer Center, Houston, Texas, 77054, USA. (19) Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. Department of ObGyn, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. (20) Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. (21) Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. Institute for Applied Cancer Science, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA. (22) Institute for Health Transformation, The University of Texas System, Houston, Texas 77030, USA.
