The Oxford Classic Links Epithelial-to-Mesenchymal Transition to Immunosuppression in Poor Prognosis Ovarian Cancers

Hu, Zhiyuan; Cunnea, Paula; Zhong, Zhe; Osagie, Oloruntoba I.; Campo, Leticia; Artibani, Mara; Nixon, Katherine; Ploski, Jennifer; González, Laura Santana; Alsaadi, Abdulkhaliq; Wietek, Nina; Damato, Stephen; Dhar, Sunanda; Blagden, Sarah P.; Yau, Christopher; Hester, Joanna; Albukhari, Ashwag; Aboagye, Eric O.; Fotopoulou, Christina; Ahmed, Ahmed

doi:10.1158/1078-0432.ccr-20-2782

Cited by 21 publications

(16 citation statements)

References 54 publications

(66 reference statements)

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“…To test this assumption, we next quantified the EMT cell state in the OXO-PCR samples using our recently described deconvolution-based classifier ( 22 , 23 ). This analysis revealed that MRD cells are particularly enriched in genes belonging to the EMT signature.…”

Section: Resultsmentioning

confidence: 99%

“…To test these alternatives, we compared the adipocyte-like gene signature between EMT-high and EMT-low prechemotherapy tumors using publicly available data sets of prechemotherapy HGSOC, TCGA ( 12 ), and the Australian Ovarian Cancer Study (AOCS) ( 24 ). We divided the samples according to our previously described EMT score ( 22 , 23 ) into EMT-high and EMT-low.…”

Section: Resultsmentioning

confidence: 99%

“…To test these alternatives, we compared the adipocyte-like gene signature between EMT-high and EMT-low pre-chemotherapy tumors using publicly available datasets of pre-chemotherapy HGSOC, The Cancer Genome Atlas (TCGA) (12) and the Australian Ovarian Cancer Study (AOCS) (24). We divided the samples according to our previously described EMT score (22,23) into EMT-high and EMT-low. Our analysis indicated that many genes from the adipocyte-like gene signature showed significantly higher expression in the EMT-high group (Figure 5D).…”

Section: Mrd Cells Show Mesenchymal Characteristicsmentioning

confidence: 99%

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Adipocyte-like signature in ovarian cancer minimal residual disease identifies metabolic vulnerabilities of tumor initiating cells

Artibani¹,

Masuda²,

Hu³

et al. 2021

JCI Insight

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Similar to tumor initiating cells (TICs), minimal residual disease (MRD) is capable of re-initiating tumors and causing recurrence. However, the molecular characteristics of solid tumor MRD cells and drivers of their survival have remained elusive. Here we performed dense multi-region transcriptomics analysis of paired biopsies from 17 ovarian cancer patients before and after chemotherapy. We reveal that while MRD cells share important molecular signatures with TICs, they are also characterized by an adipocyte-like gene expression signature and a portion of them had undergone epithelialmesenchymal transition (EMT). In a cell culture MRD model, MRD-mimic cells show the same phenotype and are dependent on fatty acid oxidation for survival and resistance to cytotoxic agents. These findings identify EMT and FAO as attractive targets to eradicate MRD in ovarian cancer and make a compelling case for the further testing of FAO inhibitors in treating MRD.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Mrd Cells Show Mesenchymal Characteristicsmentioning

confidence: 99%

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Adipocyte-like signature in ovarian cancer minimal residual disease identifies metabolic vulnerabilities of tumor initiating cells

Artibani¹,

Masuda²,

Hu³

et al. 2021

JCI Insight

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“…Further, the spatial analysis of the TME revealed significant stromalto-stromal metacluster spatial interactions in the HRwt tumors, suggesting the presence of physical and biochemical barriers which can further promote therapy resistance 14,23,24 . Moreover, we found that the HRwt tumors contained an increased proportion of tumor cells with an EMT phenotype without tumor-immune spatial interactions, which also could contribute to chemoresistance [25][26][27] . Altogether, the stromal dominance, tumor cell EMT functional states, and decreased immune surveillance can contribute to the poor prognosis of the HRwt tumors.…”

Section: Spatial Cell-cell Interactions Suggest Enhanced Immunosurveimentioning

confidence: 86%

Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer

Launonen

Lyytikäinen

Casado

et al. 2021

Preprint

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The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes. We aimed to discover how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment. Using a highly multiplex immunofluorescence and image analysis on 112 tumor cores we generated single-cell spatial data for 21 markers in 124,623 single cells from 31 tumors with BRCA1/2 mutation (BRCA1/2mut), and 13 tumors without any alterations in HR genes (HRwt). We identified a phenotypically distinct tumor microenvironment in the BRCA1/2mut tumors with evidence of increased immunosurveillance. Importantly, we found an opposing prognostic role of a proliferative tumor-cell phenotypic subpopulation in the HR-genotypes, which associated with enhanced spatial interactions in the tumor-immune cellular communities. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the premise to improve immunotherapeutic strategies and patient stratification in HGSC.

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“…TWIST1 was suggested to be a regulator of EOC stemness through controlling stem cell differentiation via regulation of miR-199a and miR-214 [31][32][33] . Furthermore, increased TWIST1 expression in CSCs has been shown to promote their differentiation into mesenchymal cells with CSC-like properties and capacity for migration [32,34] . Profiling of HGSOC tumors using the Oxford Classic classifier for molecular stratification of tumors demonstrated that EMT-high tumors were associated with poor survival and linked to immunosuppression [35] .…”

Section: Introductionmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer

Rinne¹,

Christie²,

Ardasheva³

et al. 2021

CDR

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The survival rates for women with ovarian cancer have shown scant improvement in recent years, with a 5-year survival rate of less than 40% for women diagnosed with advanced ovarian cancer. High-grade serous ovarian cancer (HGSOC) is the most lethal subtype where the majority of women develop recurrent disease and chemotherapy resistance, despite over 70%-80% of patients initially responding to platinum-based chemotherapy. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates many vital processes such as cell growth, survival and metabolism. However, this pathway is frequently dysregulated in cancers including different subtypes of ovarian cancer, through amplification or somatic mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), amplification of AKT isoforms, or deletion or inactivation of PTEN. Further evidence indicates a role for the PI3K/AKT/mTOR pathway in the development of chemotherapy resistance in ovarian cancer. Thus, targeting key nodes of the PI3K/AKT/mTOR pathway is a potential therapeutic prospect. In this review, we outline dysregulation of PI3K signaling in ovarian cancer, with a particular emphasis on HGSOC and platinum-resistant disease. We review preclinical evidence for inhibitors of the main components of the PI3K pathway and highlight past, current and upcoming trials in ovarian cancers for different inhibitors of the pathway. Whilst no inhibitors of the PI3K/AKT/mTOR pathway have thus far advanced to the clinic for the treatment of ovarian cancer, several

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The Oxford Classic Links Epithelial-to-Mesenchymal Transition to Immunosuppression in Poor Prognosis Ovarian Cancers

Cited by 21 publications

References 54 publications

Adipocyte-like signature in ovarian cancer minimal residual disease identifies metabolic vulnerabilities of tumor initiating cells

Adipocyte-like signature in ovarian cancer minimal residual disease identifies metabolic vulnerabilities of tumor initiating cells

Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer

Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer

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