The intercellular signaling network of ovarian cancer metastases
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ABSTRACT:
PROVIDER: PRJEB45800 | ENA |
REPOSITORIES: ENA
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Project description:Background: Transcoelomic spread is the major route of metastasis of ovarian high-grade serous carcinoma (HGSC) with the omentum as the major metastatic site. Its unique tumor microenvironment with its large populations of adipocytes, mesothelial cells and immune cells establishes an intercellular signaling network that is instrumental for metastatic growth yet poorly understood. Methods: Based on transcriptomic analysis of tumor cells, tumor-associated immune and stroma cells we defined intercellular signaling pathways for 284 cytokines and growth factors and their cognate receptors after bioinformatic adjustment for contaminating cell types. The significance of individual components of this network was validated by analyzing clinical correlations and potentially pro-metastatic functions, including tumor cell migration, pro-inflammatory signal transduction and TAM expansion. Results: The data show an unexpected prominent role of host cells, and in particular of omental adipocytes, mesothelial cells and fibroblasts (CAF), in sustaining this signaling network. These cells, rather than tumor cells, are the major source of most cytokines and growth factors in the omental microenvironment (n=176 versus n=13). Many of these factors target tumor cells, are linked to metastasis and are associated with a short survival. Likewise, tumor stroma cells play a major role in both extracellular-matrix-triggered and lipid-mediated signaling. We have verified the functional significance of our observations for three exemplary instances. We show that the omental microenvironment (i) stimulates tumor cell migration via WNT4 which is highly expressed by CAF; (ii) induces pro-tumorigenic TAM proliferation in conjunction with high CSF1 expression by omental stroma cells and (iii) triggers pro-inflammatory signaling, at least in part via a HSP70 – NFkB pathway. Conclusions: The intercellular signaling network of omental metastases is majorly dependent on factors secreted by immune and stroma cells to provide an environment that supports ovarian HGSC progression. Clinically relevant pathways within this network represent novel options for therapeutic intervention.
2021-11-25 | PXD028248 | Pride
Project description:Primary cells from high grade serous ovarian carcinoma patients, derived from ascites and omentum were sequenced to study signaling networks.
2021-11-01 | E-MTAB-10611 | biostudies-arrayexpress
Project description:Matched primary ovarian cancer, omental metastases, and non-omental metastases from 10 patients with high-grade serous ovarian carcinoma
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Project description:Our data suggest that neoadjuvant chemotherapy enhances anti-cancer responses of T cells in peritoneal metastases of patients with high-grade serous ovarian cancer but does not decrease levels of immune checkpoint molecules, providing a rationale for sequential chemo-immunotherapy. tRNA was isolated from 35 omental tissue samples of HGSOC metastases either pre or post NACT treatment. RNASeq was performed on poly-A selected mRNA fragments, 100 b.p paired end, and strand specific, on average 40 million reads per sample.
2016-07-27 | E-GEOD-71340 | biostudies-arrayexpress
Project description:Our data suggest that neoadjuvant chemotherapy enhances anti-cancer responses of T cells in peritoneal metastases of patients with high-grade serous ovarian cancer but does not decrease levels of immune checkpoint molecules, providing a rationale for sequential chemo-immunotherapy.
2016-07-27 | GSE71340 | GEO
Project description:Inhibiting STAT3 signaling reduces tumor progression, metastases and chemoresistance, however the precise molecular mechanism has not been fully delineated in ovarian cancer. Methods: In this study, we generated STAT3 knockout (KO) ovarian cancer cell lines. Effect of STAT3 KO on cell proliferation, migration and spheroid formation was assessed in vitro and effect on in vivo tumor growth was tested using several tumor xenograft models. We used multi-omic genome-wide profiling to identify multi-level (Bru-Seq, RNA-Seq, and MS Proteomic) expression signatures of STAT3 KO ovarian cancer cells.
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Project description:The functional status of the tumor repressor protein (TP53 or TRP53) is a defining feature of ovarian cancer. Mutant or null alleles of TP53 are expressed in greater than 90% of all high-grade serous adenocarcinomas. Wild type TP53 is elevated in low-grade serous adenocarcinomas in women and in our Pten/Kras/Amhr2-Cre mutant mouse model. Disruption of the Trp53 gene in this mouse model did not lead to high-grade ovarian cancer but did increase expression of estrogen receptor alpha (ERalpha; ESR1) and markedly enhanced the responsiveness of these cells to estrogen. Specifically, when Trp53 positive and Trp53 null mutant mice were treated with estradiol or vehicle, only the Trp53 null and Esr1 positive tumors respond vigorously to estradiol in vivo and exhibit features characteristic of high-grade type ovarian cancer: invasive growth into the ovarian stroma, rampant metastases to the peritoneal cavity and signs of genomic instability. Estrogen promoted and progesterone suppressed the growth of Trp53 null ovarian tumors and tumor cells injected intraperitoneally (IP), subcutaneously (SC) or when grown in matrigel. Exposure of the Trp53 depleted cells to estrogen also has a profound impact on the tumor microenvironment and immune-related events. These results led to the new paradigm that TRP53 status is related to the susceptibility of transformed ovarian surface epithelial (OSE) cells to estradiol-induced metastases and genomic instability. This novel finding is relevant not only for women during their reproductive years but also for women on hormone (estradiol) replacement therapies. A direct comparison of ovarian surface epithelia cells from two different genotype mice
2014-03-21 | E-GEOD-51095 | biostudies-arrayexpress
Project description:MSC stimulate ovarian tumor growth during intercellular communication but reduce tumorigenicity after fusion with ovarian cancer cells
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Project description:The distinction between primary and secondary ovarian tumors may be challenging for pathologists. We performed transcriptomic analysis in order to discriminate between primary ovarian tumors and ovarian metastases after primary breast cancer. We performed genomic analysis on tumor paired samples (breast/ovary) in order to know if genomic profiles could help for the discrimination of primary ovarian tumors and ovarian metastases after primary breast cancer.
2010-04-14 | GSE20565 | GEO
Project description:The functional status of the tumor repressor protein (TP53 or TRP53) is a defining feature of ovarian cancer. Mutant or null alleles of TP53 are expressed in greater than 90% of all high-grade serous adenocarcinomas. Wild type TP53 is elevated in low-grade serous adenocarcinomas in women and in our Pten/Kras/Amhr2-Cre mutant mouse model. Disruption of the Trp53 gene in this mouse model did not lead to high-grade ovarian cancer but did increase expression of estrogen receptor alpha (ERalpha; ESR1) and markedly enhanced the responsiveness of these cells to estrogen. Specifically, when Trp53 positive and Trp53 null mutant mice were treated with estradiol or vehicle, only the Trp53 null and Esr1 positive tumors respond vigorously to estradiol in vivo and exhibit features characteristic of high-grade type ovarian cancer: invasive growth into the ovarian stroma, rampant metastases to the peritoneal cavity and signs of genomic instability. Estrogen promoted and progesterone suppressed the growth of Trp53 null ovarian tumors and tumor cells injected intraperitoneally (IP), subcutaneously (SC) or when grown in matrigel. Exposure of the Trp53 depleted cells to estrogen also has a profound impact on the tumor microenvironment and immune-related events. These results led to the new paradigm that TRP53 status is related to the susceptibility of transformed ovarian surface epithelial (OSE) cells to estradiol-induced metastases and genomic instability. This novel finding is relevant not only for women during their reproductive years but also for women on hormone (estradiol) replacement therapies.
2014-03-21 | GSE51095 | GEO