Gene expression analysis of matched ovarian primary tumors and peritoneal metastasis

Malek, Joel A.; Martinez, Alejandra; Mery-Lamarche, Eliane; Ferron, Gwénaël; Huang, Ruby Yun‐Ju; Raynaud, Christophe M.; Jouve, Eva; Thiery, Jean Paul; Querleu, Denis; Rafii, Arash

doi:10.1186/1479-5876-10-121

Cited by 21 publications

(27 citation statements)

References 20 publications

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“…This is analogous to studies in liver, breast and colon cancer where cancer initiating cells demonstrate preferential phosphorylation of STAT3 (30, 37, 38). Interestingly, it has been reported that the JAK-STAT pathway is upregulated in metastatic ovarian cancer cells versus primary tissue (39) and we observed that in vivo inhibition of STAT3 phosphorylation with a JAK2 inhibitor was associated with near complete loss of metastasis. This strongly implicates this pathway, in ovarian cancer metastasis.…”

Section: Discussionmentioning

confidence: 51%

CD24+ Ovarian Cancer Cells Are Enriched for Cancer-Initiating Cells and Dependent on JAK2 Signaling for Growth and Metastasis

Burgos-Ojeda

McLean

et al. 2015

Molecular Cancer Therapeutics

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Ovarian cancer is known to be composed of distinct populations of cancer cells, some of which demonstrate increased capacity for cancer initiation and/or metastasis. The study of human cancer cell populations is difficult due to long requirements for tumor growth, inter-patient variability and the need for tumor growth in immune-deficient mice. We therefore characterized the cancer initiation capacity of distinct cancer cell populations in a transgenic murine model of ovarian cancer. In this model, conditional deletion of Apc, Pten, and Trp53 in the ovarian surface epithelium (OSE) results in the generation of high grade metastatic ovarian carcinomas. Cell lines derived from these murine tumors express numerous putative stem cell markers including CD24, CD44, CD90, CD117, CD133 and ALDH. We show that CD24+ and CD133+ cells have increased tumor sphere forming capacity. CD133+ cells demonstrated a trend for increased tumor initiation while CD24+ cells vs CD24− cells, had significantly greater tumor initiation and tumor growth capacity. No preferential tumor initiating or growth capacity was observed for CD44+, CD90+, CD117+, or ALDH+ versus their negative counterparts. We have found that CD24+ cells, compared to CD24− cells, have increased phosphorylation of STAT3 and increased expression of STAT3 target Nanog and c-myc. JAK2 inhibition of STAT3 phosphorylation preferentially induced cytotoxicity in CD24+ cells. In vivo JAK2 inhibitor therapy dramatically reduced tumor metastases, and prolonged overall survival. These findings indicate that CD24+ cells play a role in tumor migration and metastasis and support JAK2 as a therapeutic target in ovarian cancer.

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Section: Discussionmentioning

confidence: 51%

CD24+ Ovarian Cancer Cells Are Enriched for Cancer-Initiating Cells and Dependent on JAK2 Signaling for Growth and Metastasis

Burgos-Ojeda

McLean

et al. 2015

Molecular Cancer Therapeutics

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“…We applied the MASH scheme to paired tumour samples comparing primary tumour with metastatic/recurrent disease, including ascitic cells from the same patient. Intriguingly, regardless of the initial subtype of the primary ovarian tumour sample, the subsequent omental metastasis GSE30587 , peritoneum metastasis FRTLO and/or ascitic cells of patients (GSE94598) at recurrent disease consistently showed an increase in the percentage of Mes or Stem‐A subtype (Figure A). The same trend of Mes or Stem‐A enrichment was also seen in platinum‐resistant relapsed disease compared with the primary tumours in two separate independent cohorts, E‐MTAB‐611 and ICGC‐AOCS (see supplementary material, Supplementary materials and methods).…”

Section: Resultsmentioning

confidence: 98%

Decoding transcriptomic intra‐tumour heterogeneity to guide personalised medicine in ovarian cancer

Tan

Heong

et al. 2018

The Journal of Pathology

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The evaluation of intra‐tumour heterogeneity (ITH) from a transcriptomic point of view is limited. Single‐cell cancer studies reveal significant genomic and transcriptomic ITH within a tumour and it is no longer adequate to employ single‐subtype assignment as this does not acknowledge the ITH that exists. Molecular assessment of subtype heterogeneity (MASH) was developed to comprehensively report on the composition of all transcriptomic subtypes within a tumour lesion. Using MASH on 3431 ovarian cancer samples, correlation and association analyses with survival, metastasis and clinical outcomes were performed to assess the impact of subtype composition as a surrogate for ITH. The association was validated on two independent cohorts. We identified that 30% of ovarian tumours consist of two or more subtypes. When biological features of the subtype constituents were examined, we identified significant impact on clinical outcomes with the presence of poor prognostic subtypes (Mes or Stem‐A). Poorer outcomes correlated with having higher degrees of poor prognostic subtype populations within the tumour. Subtype prediction in several independent datasets reflected a similar prognostic trend. In addition, paired analysis of primary and recurrent/metastatic tumours demonstrated Mes and/or Stem‐A subtypes predominated in recurrent and metastatic tumours regardless of the original primary subtype. Given the biological and prognostic value in delineating individual subtypes within a tumour, a clinically applicable MASH assay using NanoString® technology was developed as a classification tool to comprehensively describe constituents of molecular subtypes. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…As reported in the table, the number of differentially expressed genes is less than one quarter of the number of differentially expressed circRNA candidates. This apparent large disparity between linear and circRNA differential expression is primarily due to a heterogeneous cancer transcriptome which often shows less reproducibility between patients and therefore masks any expression differences between the samples [7]. Nonetheless, circRNAs have a greater intracellular stability [21] due to their resistance to RNA exonucleases; therefore, they exhibit a robust expression pattern and may thus be more suitable candidates in identifying differences between primary tumor and metastatic lesions.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously described copy number variation (CNV) and gene expression analysis of matched ovarian primary tumors and peritoneal metastases, and reported targeting of several specific pathways that play a role in ovarian cancer metastasis both at genomic and transcriptomic levels [7, 8]. Many other studies have also focused on delineating the gene expression signatures for disease prognosis and therapeutic responses [9–11].…”

Section: Introductionmentioning

confidence: 99%

Altered expression pattern of circular RNAs in primary and metastatic sites of epithelial ovarian carcinoma

et al. 2016

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Recently, a class of endogenous species of RNA called circular RNA (circRNA) has been shown to regulate gene expression in mammals and their role in cellular function is just beginning to be understood. To investigate the role of circRNAs in ovarian cancer, we performed paired-end RNA sequencing of primary sites, peritoneal and lymph node metastases from three patients with stage IIIC ovarian cancer. We developed an in-house computational pipeline to identify and characterize the circRNA expression from paired-end RNA-Seq libraries. This pipeline revealed thousands of circular isoforms in Epithelial Ovarian Carcinoma (EOC). These circRNAs are enriched for potentially effective miRNA seed matches. A significantly larger number of circRNAs are differentially expressed between tumor sites than mRNAs. Circular and linear expression exhibits an inverse trend for many cancer related pathways and signaling pathways like NFkB, PI3k/AKT and TGF-β typically activated for mRNA in metastases are inhibited for circRNA expression. Further, circRNAs show a more robust expression pattern across patients than mRNA forms indicating their suitability as biomarkers in highly heterogeneous cancer transcriptomes. The consistency of circular RNA expression may offer new candidates for cancer treatment and prognosis.

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Gene expression analysis of matched ovarian primary tumors and peritoneal metastasis

Cited by 21 publications

References 20 publications

CD24+ Ovarian Cancer Cells Are Enriched for Cancer-Initiating Cells and Dependent on JAK2 Signaling for Growth and Metastasis

CD24+ Ovarian Cancer Cells Are Enriched for Cancer-Initiating Cells and Dependent on JAK2 Signaling for Growth and Metastasis

Decoding transcriptomic intra‐tumour heterogeneity to guide personalised medicine in ovarian cancer

Altered expression pattern of circular RNAs in primary and metastatic sites of epithelial ovarian carcinoma

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