PRKCI promotes immune suppression in ovarian cancer

Sharmistha Sarkar; Christopher A. Bristow; Prasenjit Dey; Kunal Rai; Ruth Perets; Alejandra Ramirez-Cardenas; Shruti Malasi; Emmet Huang-Hobbs; Monika Haemmerle; Sherry Y. Wu; Michael McGuire; Alexei Protopopov; Shan Jiang; Joyce F. Liu; Michelle S. Hirsch; Qing Chang; Alexander J. Lazar; Anil K. Sood; Ronny Drapkin; Ronald DePinho; Giulio Draetta; Lynda Chin

doi:10.1101/gad.296640.117

PRKCI promotes immune suppression in ovarian cancer

Sharmistha Sarkar, Christopher A. Bristow, Prasenjit Dey, Kunal Rai, Ruth Perets, Alejandra Ramirez-Cardenas, Shruti Malasi, Emmet Huang-Hobbs, Monika Haemmerle, Sherry Y. Wu, Michael McGuire, Alexei Protopopov, Shan Jiang, Joyce F. Liu, Michelle S. Hirsch, Qing Chang, Alexander J. Lazar, Anil K. Sood, Ronny Drapkin, Ronald DePinhoGiulio Draetta, Lynda Chin

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

Abstract

A key feature of high-grade serous ovarian carcinoma (HGSOC) is frequent amplification of the 3q26 locus harboring PRKC-ι (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 TNFα 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 TNFα 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.

Original language	English (US)
Pages (from-to)	1109-1121
Number of pages	13
Journal	Genes and Development
Volume	31
Issue number	11
DOIs	https://doi.org/10.1101/gad.296640.117
State	Published - 2017

Keywords

Ovarian cancer
PRKCI
YAP

ASJC Scopus subject areas

Genetics
Developmental Biology

MD Anderson CCSG core facilities

Genetically Engineered Mouse Facility
Research Animal Support Facility

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10.1101/gad.296640.117

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Sarkar, S., Bristow, C. A., Dey, P., Rai, K., Perets, R., Ramirez-Cardenas, A., Malasi, S., Huang-Hobbs, E., Haemmerle, M., Wu, S. Y., McGuire, M., Protopopov, A., Jiang, S., Liu, J. F., Hirsch, M. S., Chang, Q., Lazar, A. J., Sood, A. K., Drapkin, R., ... Chin, L. (2017). PRKCI promotes immune suppression in ovarian cancer. Genes and Development, 31(11), 1109-1121. https://doi.org/10.1101/gad.296640.117

Sarkar, S, Bristow, CA, Dey, P, Rai, K, Perets, R, Ramirez-Cardenas, A, Malasi, S, Huang-Hobbs, E, Haemmerle, M, Wu, SY, McGuire, M, Protopopov, A, Jiang, S, Liu, JF, Hirsch, MS, Chang, Q , Lazar, AJ , Sood, AK, Drapkin, R, DePinho, R , Draetta, G & Chin, L 2017, 'PRKCI promotes immune suppression in ovarian cancer', Genes and Development, vol. 31, no. 11, pp. 1109-1121. https://doi.org/10.1101/gad.296640.117

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title = "PRKCI promotes immune suppression in ovarian cancer",

abstract = "A key feature of high-grade serous ovarian carcinoma (HGSOC) is frequent amplification of the 3q26 locus harboring PRKC-ι (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 TNFα 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 TNFα 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.",

keywords = "Ovarian cancer, PRKCI, YAP",

author = "Sharmistha Sarkar and Bristow, {Christopher A.} and Prasenjit Dey and Kunal Rai and Ruth Perets and Alejandra Ramirez-Cardenas and Shruti Malasi and Emmet Huang-Hobbs and Monika Haemmerle and Wu, {Sherry Y.} and Michael McGuire and Alexei Protopopov and Shan Jiang and Liu, {Joyce F.} and Hirsch, {Michelle S.} and Qing Chang and Lazar, {Alexander J.} and Sood, {Anil K.} and Ronny Drapkin and Ronald DePinho and Giulio Draetta and Lynda Chin",

note = "Publisher Copyright: {\textcopyright} 2017 Sarkar et al.",

year = "2017",

doi = "10.1101/gad.296640.117",

language = "English (US)",

volume = "31",

pages = "1109--1121",

journal = "Genes and Development",

issn = "0890-9369",

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T1 - PRKCI promotes immune suppression in ovarian cancer

AU - Sarkar, Sharmistha

AU - Bristow, Christopher A.

AU - Dey, Prasenjit

AU - Rai, Kunal

AU - Perets, Ruth

AU - Ramirez-Cardenas, Alejandra

AU - Malasi, Shruti

AU - Huang-Hobbs, Emmet

AU - Haemmerle, Monika

AU - Wu, Sherry Y.

AU - McGuire, Michael

AU - Protopopov, Alexei

AU - Jiang, Shan

AU - Liu, Joyce F.

AU - Hirsch, Michelle S.

AU - Chang, Qing

AU - Lazar, Alexander J.

AU - Sood, Anil K.

AU - Drapkin, Ronny

AU - DePinho, Ronald

AU - Draetta, Giulio

AU - Chin, Lynda

PY - 2017

Y1 - 2017

N2 - A key feature of high-grade serous ovarian carcinoma (HGSOC) is frequent amplification of the 3q26 locus harboring PRKC-ι (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 TNFα 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 TNFα 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.

AB - A key feature of high-grade serous ovarian carcinoma (HGSOC) is frequent amplification of the 3q26 locus harboring PRKC-ι (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 TNFα 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 TNFα 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.

KW - Ovarian cancer

KW - PRKCI

KW - YAP

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SN - 0890-9369

VL - 31

SP - 1109

EP - 1121

JO - Genes and Development

JF - Genes and Development

IS - 11

ER -

PRKCI promotes immune suppression in ovarian cancer

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

Access to Document

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