Project description:Ovarian cancer is the most lethal malignancy in the United States. In the year 2012, there will be an estimated 22,280 new cases and 15,500 deaths from ovarian cancer in the country (Siegel et al., 2012). While studies on ovarian cancer pathogenesis were mainly focused on the epithelial component of the tumor, understanding in the role of cancer associated fibroblasts (CAFs) in ovarian cancer progression is limited. We hypothesized that comparing the gene expression profiles of different components from laser capture microdissected ovarian tissue will allow us to identify an ovarian CAFs specific gene signature which accounts for the supportive role of CAFs in ovarian cancer progression. In this study, gene expression profiling was completed for 31 cancer stroma samples and 32 samples of epithelial component from high grade serous ovarian cancer patients. 8 microdissected normal ovarian stroma and 6 normal human ovarian surface epithelium (HOSE) samples were also included in the study. By comparing the expression data from cancer stroma against that from normal stroma, cancer cells and HOSE, we identified a set of differential expressed genes in ovarian CAFs which showed correlation with cancer patient survival. Further study on these genes can reveal their roles in ovarian cancer progression and pathogenesis. Ultimately, ovarian CAFs specified genes identified in this study may aid in the classification and enhancement of patient outcome. Transcriptome profiling analyses were performed on 31 laser microdissected cancer associated stroma samples, 32 epithelial tumor samples from high grade serous ovarian cancer patients, 8 microdissected normal ovarian stroma samples and 6 ovarian surface epthelium (HOSE) samples using the Affymetrix human genome U133 Plus 2.0 microarray.
Project description:Recent studies indicate that cancer-associated fibroblasts (CAFs) are phenotypically and functionally heterogeneous. However, little is known about CAF subtypes and the roles they play in cancer progression. Here we identify and characterize two CAF subtypes that coexist within high grade serous ovarian cancers: Fibroblast activation protein (FAP)-high (FH) CAFs resemble the classical myofibroblast-type CAF, whereas FAP-low (FL) CAFs possesses a preadipocyte-like molecular signature.
Project description:Recent studies indicate that cancer-associated fibroblasts (CAFs) are phenotypically and functionally heterogeneous. However, little is known about CAF subtypes and the roles they play in cancer progression. Here we identify and characterize two CAF subtypes that coexist within high grade serous ovarian cancers: Fibroblast activation protein (FAP)-high (FH) CAFs resemble the classical myofibroblast-type CAF, whereas FAP-low (FL) CAFs possesses a preadipocyte-like molecular signature.
Project description:Ovarian cancer is the most lethal malignancy in the United States. In the year 2012, there will be an estimated 22,280 new cases and 15,500 deaths from ovarian cancer in the country (Siegel et al., 2012). While studies on ovarian cancer pathogenesis were mainly focused on the epithelial component of the tumor, understanding in the role of cancer associated fibroblasts (CAFs) in ovarian cancer progression is limited. We hypothesized that comparing the gene expression profiles of different components from laser capture microdissected ovarian tissue will allow us to identify an ovarian CAFs specific gene signature which accounts for the supportive role of CAFs in ovarian cancer progression. In this study, gene expression profiling was completed for 31 cancer stroma samples and 32 samples of epithelial component from high grade serous ovarian cancer patients. 8 microdissected normal ovarian stroma and 6 normal human ovarian surface epithelium (HOSE) samples were also included in the study. By comparing the expression data from cancer stroma against that from normal stroma, cancer cells and HOSE, we identified a set of differential expressed genes in ovarian CAFs which showed correlation with cancer patient survival. Further study on these genes can reveal their roles in ovarian cancer progression and pathogenesis. Ultimately, ovarian CAFs specified genes identified in this study may aid in the classification and enhancement of patient outcome.
Project description:Tumor associated macrophages from high grade serous ovarian cancer ascites were treated with 1 μM of the Prostacyclin analoga MRE and DMSO (as solvent control). The aim of this experiment is to see which effect the Prostacyclin analoga has on RNA expression (activation of signaling pathways). Background: Prostacyclin receptor expression is elevated in TAMs. Prostacyclinsynthase expression was detected mainly in CAFs.
Project description:Cancer-associated fibroblasts (CAFs) play a pivotal cancer-supportive role, yet CAF-targeted therapies remain elusive. Through spatial transcriptomics and single-cell RNA sequencing, we investigated the role of nicotinamide N-methyltransferase (NNMT) in high-grade serous ovarian cancer (HGSOC). Mechanistically, NNMT-induced H3K27me3 hypomethylation drives complement secretion from CAFs, attracting immunosuppressive myeloid-derived suppressor cells (MDSCs) to the tumor. NNMT knockout in immunocompetent mice impaired tumor growth in syngeneic ovarian, breast, and colon tumor models through enhanced CD8+ T cell activation. Using high-throughput screening, we developed a potent and specific NNMT inhibitor that reduces tumor burden and metastasis in multiple murine cancer models and restores immune checkpoint blockade efficacy by decreasing CAF-mediated MDSC recruitment and reinvigorating CD8⁺ T cell activation. Our findings establish NNMT as a central CAF regulator and promising therapeutic target to mitigate immunosuppression in the tumor microenvironment.
Project description:Cancer-associated fibroblasts (CAFs) play a pivotal cancer-supportive role, yet CAF-targeted therapies remain elusive. Through spatial transcriptomics and single-cell RNA sequencing, we identified nicotinamide N-methyltransferase (NNMT) as a central CAF regulator in high-grade serous ovarian cancer (HGSOC) patients. Mechanistically, NNMT-induced H3K27me3 hypomethylation drives complement secretion from CAFs, attracting immunosuppressive myeloid-derived suppressor cells (MDSCs) to the tumor. Using high-throughput screening, we developed a potent, specific NNMT inhibitor that reduces tumor burden in multiple murine cancer models and restores immune checkpoint blockade efficacy by decreasing CAF-mediated MDSC recruitment and reinvigorating CD8⁺ T cell activation. Our findings establish NNMT as an essential CAF regulator and promising therapeutic target to mitigate immunosuppression in the tumor microenvironment.
Project description:To demonstrate the use of a whole-genome oligonucleotide array to perform expression profiling on a series of microdissected late-stage, high-grade papillary serous ovarian adenocarcinomas to establish a prognostic gene signature correlating with survival and to identify novel survival factors in ovarian cancer. Advanced stage papillary serous tumors of the ovary are responsible for the majority of ovarian cancer deaths, yet the molecular determinants modulating patient survival are poorly characterized. We identify and validate a prognostic gene expression signature correlating with survival in a series of microdissected serous ovarian tumors. Experiment Overall Design: We identified 53 advanced stage, high-grade primary tumor specimens and 10 normal ovarian surface epithelium (OSE) brushings.
Project description:Low grade serous ovarian cancer (LGSC) is a rare subtype of ovarian cancer, characterized by a slow growth rate, resistance to current treatment regimens, multiple recurrences and poor survival. LGSC arise from serous borderline tumor (SBT), however the mechanism of transformation is poorly understood. To better understand the biology of serous ovarian tumors, we performed whole proteome profiling of LGSC, SBT and the more common high grade serous (HGSC) ovarian tumors. Proteins associated with the tumor microenvironment were differentially expressed between LGSC and SBT or HGSC. In particular, fibroblast activation protein (FAP), a protein expressed in cancer associated fibroblasts, is abundantly expressed in LGSC. Furthermore, Tregs and M2 macrophages are more abundant in the stroma of LGSC compared to SBT. Together these data suggest that the tumor microenvironment provides a supportive environment for LGSC tumorigenesis and progression, and that targeting the tumor microenvironment of LGSC may be a viable therapeutic strategy.