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Netrin and its dependence receptors are mediators of high-grade serous ovarian cancer cell survival

ABSTRACT: We previously showed that DYRK1A is essential for ovarian cancer spheroid cell survival. DYRK1A regulates transcription by assembling the DREAM repressor complex and also regulates RNA polymerase II. However, the present understanding of how DYRK1A regulates transcription in high-grade serous ovarian cancer (HGSOC) spheroid cells to promote quiescence and survival is lacking. Here we performed GO-CRISPR screens in a panel of HGSOC spheroid cells in combination with transcriptional analyses of DYRK1A deficient spheroid cells. We identified netrin signaling components as essential factors of HGSOC spheroid cell survival. Netrin is well-characterized in axon development but has recently been implicated in other cancer types. We found that knockout of netrin ligands or receptors affects viability of spheroid cells. Netrin ligands and receptors are upregulated in HGSOC cells in suspension conditions. Together, this work suggests that the netrin signaling pathway may be a potential therapeutic target to specifically eliminate spheroid cells in HGSOC and highlights it as an important area requiring further investigation in the context of ovarian cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE190294 | GEO | 2023/04/01

REPOSITORIES: GEO

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Identification of MRCKA as an integral component of ovarian cancer signaling and a therapeutic target

Project description:High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological cancer with few effective targeted therapies. HGSOC tumors exhibit genomic instability with frequent alterations in the protein kinome; however, only a small fraction of the kinome has been therapeutically targeted in HGSOC. Using multiplexed inhibitor beads and mass spectrometry (MIB-MS), we mapped the kinome landscape of HGSOC patient tumors and tumors isolated from HGSOC patient-derived xenograft (PDX) models. Kinome profiling of HGSOC tumors uncovered a prevalent MIB-MS kinome signature consisting of established HGSOC driver kinases, as well as several kinases previously unexplored in HGSOC. Loss-of-function analysis targeting the tumor kinome signature in HGSOC cells nominated CDC42BPA (also known as MRCKA) as a putative therapeutic target. Characterization of MRCKA knockdown in established HGSOC cell lines demonstrated MRCKA was integral to signaling that regulated the cell cycle checkpoint and focal adhesion/ actin remodeling, and depletion of MRCKA impaired cell migration, proliferation and survival. Moreover, small molecule inhibition of MRCKA using BDP9066 inhibited cell growth and induced apoptosis in HGSOC cells, as well as blocked spheroid formation, supporting MRCKA as a novel therapeutic target for the treatment of HGSOC.

2020-02-19 | PXD015781 | Pride

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Engineered adoptive T cell therapy prolongs survival in a preclinical model of advanced stage ovarian cancer [Mouse]

Project description:Purpose: Adoptive T cell therapy using high affinity T cell receptors (TCRs) to target tumor antigens has potential for improving outcomes in high-grade serous ovarian cancer (HGSOC) patients. Ovarian tumors develop a hostile, multicomponent tumor microenvironment containing suppressive cells, inhibitory ligands, and soluble factors that facilitate evasion of anti-tumor immune responses. Developing and validating an immunocompetent mouse model of metastatic ovarian cancer that shares antigenic and immunosuppressive qualities of human disease would facilitate establishing effective T cell therapies. Experimental Design: We used deep transcriptome profiling and immunohistochemical analysis of human HGSOC tumors and disseminated mouse ID8VEGF tumors to compare immunologic features. We then evaluated the ability of CD8 T cells engineered to express a high-affinity TCR specific for mesothelin, an ovarian cancer antigen, to infiltrate advanced stage ID8VEGF murine ovarian tumors and control tumor growth. Human CD8 T cells engineered to target mesothelin were also evaluated for ability to kill HLA-A2+ HGSOC lines. Results: Immunohistochemistry and gene expression profiling revealed striking similarities between tumors, including processing/presentation of similar candidate target antigens, suppressive immune cell infiltration, and expression of molecules that inhibit T cell function. Engineered T cells infiltrated mouse tumors but became progressively dysfunctional and failed to persist within tumors. Treatment with repeated doses of T cells maintained functional activity, significantly prolonging survival of mice harboring late-stage disease at treatment onset. Human CD8 T cells engineered to target mesothelin were tumoricidal for three HGSOC lines. Conclusions: Treatment with engineered T cells may have clinical applicability in patients with advanced-stage HGSOC.

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Engineered adoptive T cell therapy prolongs survival in a preclinical model of advanced stage ovarian cancer [Human]

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