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Transcriptomic Effects of SSX2 on a Prostate Cancer Cell Line

ABSTRACT: Prostate cancer is the most commonly diagnosed malignancy in the United States. While the majority of cases are cured with radiation or surgery, about 1/3 of patients will develop metastatic disease which there is no cure, and has a life expectancy of less than 5 years. Identification of antigens associated with this transition to metastatic disease is crucial for future therapies. One such antigen of interest is the SSX gene family, which are cancer/testis antigens that are associated with the epithelial to mesenchymal transition in other cancer types. Prior work has shown that, in prostate cancer, SSX expression was restricted to metastatic tissue and not primary tumor tissue which may indicate a role in disease progression. Some work has been done into the function of the SSX family, which revealed transcriptional regulator activity. But neither the targets of this activity or the function of SSX are known. Through a transcriptomics approach, we are seeking a better understanding of the different genes and pathways SSX regulates in the context of prostate cancer, and to determine if these pathways may contribute to disease progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE77811 | GEO | 2016/02/11

SECONDARY ACCESSION(S): PRJNA311607

REPOSITORIES: GEO

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Transcriptomic Effects of SSX2 on a Prostate Cancer Cell Line

Project description:Prostate cancer is the most commonly diagnosed malignancy in the United States. While the majority of cases are cured with radiation or surgery, about 1/3 of patients will develop metastatic disease which there is no cure, and has a life expectancy of less than 5 years. Identification of antigens associated with this transition to metastatic disease is crucial for future therapies. One such antigen of interest is the SSX gene family, which are cancer/testis antigens that are associated with the epithelial to mesenchymal transition in other cancer types. Prior work has shown that, in prostate cancer, SSX expression was restricted to metastatic tissue and not primary tumor tissue which may indicate a role in disease progression. Some work has been done into the function of the SSX family, which revealed transcriptional regulator activity. But neither the targets of this activity or the function of SSX are known. Through a transcriptomics approach, we are seeking a better understanding of the different genes and pathways SSX regulates in the context of prostate cancer, and to determine if these pathways may contribute to disease progression. We analyzed the 22Rv1 prostate cancer cell under three different conditions with 3 technical replicates each (9 total samples) They are as follow: KD the 22Rv1 cell line tranfected with shRNA targetted against the gene SSX2, SCR the 22Rv1 cell line transfected with a scrambled control shRNA, WT the wildtype 22Rv1 cell line

2016-02-11 | E-GEOD-77811 | biostudies-arrayexpress

KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis

Project description:Frequent truncating mutations of the histone lysine N‑methyltransferase KMT2C have been detected by whole exome sequencing studies in various cancers, including malignancies of the prostate. However, the biological consequences of these alterations in prostate cancer have not yet been elucidated. To investigate the functional impact of these mutations we deleted the C-terminal catalytic core motif of KMT2C specifically in the prostate epithelium of mice. We show here that impaired KMT2C methyltransferase activity drives proliferation and, when combined with loss of the tumour suppressor PTEN, triggers metastatic dissemination and reduces life expectancy. In our model system and human prostate cancer samples we show that KMT2C-mutated tumours activate the proliferative MYC signalling axis and fail to express the oncogene-induced cell cycle repressor p16INK4A. In addition, we observe a striking reduction in disease-free survival of patients with KMT2C-mutated prostate cancer. Thus, we identify truncated KMT2C as a driver of aggressive prostate cancer.

2022-05-02 | GSE186413 | GEO

Pten loss and RAS/MAPK activation cooperate to promote EMT and prostate cancer metastasis initiated from stem/progenitor cells

Project description:PTEN loss or PI3K/AKT signaling pathway activation correlates with human prostate cancer progression and metastasis. However, in preclinical murine models, deletion of Pten alone fails to mimic the significant metastatic burden that frequently accompanies the end stage of human disease. To identify additional pathway alterations that cooperate with PTEN loss in prostate cancer progression, we surveyed human prostate cancer tissue microarrays and found that the RAS/MAPK pathway is significantly elevated both in primary and metastatic lesions. In an attempt to model this event, we crossed conditional activatable K-rasG12D/WT mice with the prostate conditional Pten deletion model we previously generated. Although RAS activation alone cannot initiate prostate cancer development, it significantly accelerated progression caused by PTEN loss, accompanied by epithelial-to-mesenchymal transition (EMT) and macrometastasis with 100% penitence. A novel stem/progenitor subpopulation with mesenchymal characteristics was isolated from the compound mutant prostates, which was highly metastatic upon orthotopic transplantation. Importantly, inhibition of RAS/MAPK signaling by PD325901, a MEK inhibitor, significantly reduced the metastatic progression initiated from transplanted stem/progenitor cells. Collectively, these data indicate that activation of RAS/MAPK signaling serves as a potentiating second hit to alteration of the PTEN/PI3K/AKT axis and co-targeting both pathways is highly effective in preventing the development of metastatic prostate cancers. Murine mutants with prostate specific loss of Pten and K-ras activation (K-rasG12D) under regulation of the probasin promoter developed high grade, invasive prostate cancer. RNA was extracted from dissected prostate lobes from individual mutants with pathology thought to closely mimic human disease. Prostate tissue was subject to RNA extraction and hybridization on Affymetrix cDNA microarrays.

2012-02-28 | E-GEOD-34839 | biostudies-arrayexpress

Proteomics reveals the ribosome signaling pathway promoting prostate cancer progression and correlating with poor prognosis

Project description:Through digital rectal examinations and routine prostate-specific antigen (PSA) screening, early treatment of prostate cancer has become possible. However, prostate cancer is a complex and heterogeneous disease. In many patients, cancer cells can invade adjacent tissues and metastasize to other tissues, resulting in difficultly to cure. For the treatment of primary and metastatic prostate cancer, a significant problem is how to improve its survival time. Here, we collect 7 untreated primary and metastatic prostate cancer and 6 benign prostate hyperplasia samples under ultrasound guidance by experienced radiologists using the 18-G needle. Through mass spectrometry, we have completely depicted the protein atlas of primary and metastatic prostate cancer and benign prostate hyperplasia. Through bioinformatics analysis, experimental verification, and combined clinical data, we discover that the ribosome signaling pathway promotes the progression of prostate cancer and is associated with a poor prognosis. Among them, Mrpl1, Mrpl4, and Mrpl16 may be biomolecular markers for diagnosis and prognosis.

2021-09-05 | PXD028211 | iProX

Identification of novel glycoproteins expressed on human macrophage surface using glycoproteomics

Project description:Prostate cancer is a leading cause of cancer-related deaths of men in the U.S. While localized disease is highly treatable by surgical resection and radiation, cancer that has metastasized remains incurable. Immune cells that primarily scavenge debris, promote prostate cancer angiogenesis and wound repair are M2 Macrophages. They are phenotypically similar to M2 tumor-associated macrophages (M2-TAMs) have been reported to associate with solid tumors and aide in proliferation, metastasis, and resistance to therapy. As an invasive species within the tumor microenvironment, this makes M2-TAMs an ideal therapeutic target in prostate cancer. To identify novel surface antigens expressed on M2-macrophages, we developed a novel method of creating homogenous populations of human macrophages from human CD14+ monocytes in vitro. These homogenous M1 macrophages secrete pro-inflammatory cytokines and our M2 macrophages secrete anti-inflammatory cytokines as well as Vascular Endothelial Growth Factor (VEGF). To identify enriched surface glycoproteins, we then performed solid-phase extraction of N-linked glycopeptides (SPEG) followed by liquid chromatography-tandem Mass Spectrometry (LC-MS/MS) on our homogenous macrophage populations. We discovered novel glycoproteins that are enriched exclusively on human M2-macrophages relative to human M1 macrophages and human CD14+ monocytes. Lastly, we determined if these surface antigens, found enriched on M2 macrophages, were also expressed in human metastatic castrate-resistant prostate cancer (mCRPC) tissues. Using mCRPC tissues from rapid autopsies, we were able to determine M2-macrophage infiltration by using immunohistochemistry and flow cytometry. These findings highlight the presence of macrophage infiltration in human mCRPC but also surface antigens that could be used for prognosis of localized disease and for targeting strategies.

2017-03-31 | PXD005080 | Pride

Gene expression profile of SYT-SSX2-expressing C2C12 myoblasts

Project description:Synovial sarcoma is a rare malignancy characterized by the presence of a specific chromosomal translocation t(X;18) that results in the formation of a fusion protein SYT-SSX. Because it is believed that synovial sarcoma arises from mesenchymal stem or progenitor cells, we wanted to determine the changes in gene expression caused by SYT-SSX2 in untransformed mesenchymal progenitor cells - murine C2C12 myoblasts in this experiment.

2011-09-26 | GSE26562 | GEO

Proteins from formalin-fixed paraffin-embedded prostate cancer sections that predict the risk of metastatic disease

Project description:Purpose: Prostate cancer is the most frequently diagnosed cancer in men and the third leading cause of cancer related deaths among men living in developed countries. Biomarkers that predict disease outcome at the time of initial diagnosis would aid management of the disease. Experimental design: Proteins extracted from formalin-fixed paraffin-embeddded sections were identified either using LC-MALDI MS/MS of tryptic digests or after separation by one- or two-dimensional electrophoresis. A list of potential biomarker candidates, based on proposed associations with prostate cancer, was derived from the 320 identified proteins. Results: Four of the candidates: annexin A2, peroxiredoxin-1, prostate-specific antigen and zinc-alpha-2-glycoprotein, were examined by Western blotting of extracts of biopsies from men whom there was 10-year disease outcome data. Multiplexed Western blotting using cocktails of antibodies and fluor-labeled detection reagents showed that annexin A2 provided the best prediction of risk of metastatic disease. Conclusions and clinical relevance: This pilot study indicates that tumour expression of ANXA2 in diagnostic biopsies of a prostate cancer is predictive for the metastatic potential of that cancer. The potential of protein profiling of each cancer is to lead to an overall reduction in mortality from metastatic prostate cancer as well as reduced treatment associated morbidity.

2015-09-14 | PXD000963 | Pride

Genomic changes of Peripheral Blood Neutrophils throughout Prostate Cancer Progression

Project description:Bulk RNA sequencing of peripheral blood neutrophils from prostate cancer at different stages of disease progression, including localized disease, hormone-sensitive- and castration-resistant metastatic prostate cancer

2023-12-13 | GSE197609 | GEO

Pten loss and RAS/MAPK activation cooperate to promote EMT and prostate cancer metastasis initiated from stem/progenitor cells

2012-02-28 | GSE34839 | GEO

Somatic tissue engineering in mouse models reveals an actionable role for WNT pathway alterations in prostate cancer metastasis

Project description:To study genetic factors that influence the progression and therapeutic response of advanced prostate cancer, we developed a fast and flexible system that introduces genetic alterations relevant to human disease directly into the prostate glands of mice using tissue electroporation. These electroporation based genetically engineered mouse models (EPO-GEMM) recapitulate features of traditional germline models and, by modeling genetic factors linked to late stage human disease, can produce tumors that are metastatic and castration resistant. Unexpectedly, a subset of particularly metastatic tumors acquired WNT pathway alterations, which are also associated with metastatic prostate cancer in humans. Harnessing features linked to the EPO-GEMM approach, we validate the WNT pathway as a key event in driving metastatic disease, a finding that we confirm in an orthogonal approach using mouse prostate organoids. Moreover, we show that tumors harboring WNT pathway alterations are sensitive to pharmacological WNT pathway inhibition. Thus, by leveraging the power of EPO-GEMMs, our studies reveal a functional role for WNT signaling in driving prostate cancer metastasis and validate the WNT pathway as an actionable therapeutic target in metastatic prostate cancer.

2020-04-28 | GSE139340 | GEO

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