Metabolic Alterations and WNT Signaling Impact Immune Response in HGSOC

Arend, Rebecca C.; Scalise, Carly Bess; Gordon, Emily R.; Davis, Allison M.; Foxall, McKenzie E.; Johnston, Bobbi E.; Crossman, David K.; Cooper, Sara J.

doi:10.1158/1078-0432.ccr-21-2984

Cited by 11 publications

(10 citation statements)

References 63 publications

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“…We then highlighted a subset of ligands where the cognate receptor was expressed in the same non-malignant cell type suggesting the tumour subclone may directly influence the observed infiltration pattern (Table 1, Figure 4). Others have previously attempted to relate tumour-expressed ligands to differences in infiltration patterns [64][65][66] ; however, to our knowledge, this is the first study to demonstrate that subclones express different ligands which then influence non-malignant cell infiltration. Notably, these associations were largely patient-or subclone-specific.…”

Section: Discussionmentioning

confidence: 99%

Spatial transcriptomics reveals ovarian cancer subclones with distinct tumour microenvironments

Denisenko

Kock

Tan³

et al. 2022

Preprint

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High-grade serous ovarian carcinoma (HGSOC) is characterised by recurrence, chemotherapy resistance and overall poor prognosis. Genetic heterogeneity of tumour cells and the microenvironment of the tumour have been hypothesised as key determinants of treatment resistance and relapse. Here, using a combination of spatial and single cell transcriptomics (10x Visium and Chromium platforms), we examine tumour genetic heterogeneity and infiltrating populations of HGSOC samples from eight patients with variable response to neoadjuvant chemotherapy. By inferring gross copy number alterations (CNAs), we identified distinct tumour subclones co-existing within individual tumour sections. These tumour subclones have unique CNA profiles and spatial locations within each tumour section, which were further validated by ultra-low-pass whole genome sequencing. Differential expression analysis between subclones within the same section identified both tumour cell intrinsic expression differences and markers indicative of different infiltrating cell populations. The gene sets differentially expressed between subclones were significantly enriched for genes encoding plasma membrane and secreted proteins, indicative of subclone-specific microenvironments. Furthermore, we identified tumour derived ligands with variable expression levels between subclones that correlated or anticorrelated with various non-malignant cell infiltration patterns. We highlight several of these that are potentially direct tumour-stroma/immune cell relationships as the non-malignant cell type expresses a cognate receptor for the tumour derived ligand. These include predictions of CXCL10-CXCR3 mediated recruitment of T and B cells to associate with the subclones of one patient and CD47-SIRPA mediated exclusion of macrophages from association with subclones of another. Finally, we show that published HGSOC molecular subtype signatures associated with prognosis are heterogeneously expressed across tumour sections and that areas containing different tumour subclones with different infiltration patterns can match different subtypes. Our study highlights the high degree of intratumoural subclonal and infiltrative heterogeneity in HGSOC which will be critical to better understand resistance and relapse.

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Section: Discussionmentioning

confidence: 99%

Spatial transcriptomics reveals ovarian cancer subclones with distinct tumour microenvironments

Denisenko

Kock

Tan³

et al. 2022

Preprint

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“…To date, regardless of the continuous improvement and development of surgical and systematic management, the mortality of these patients has not been improved under the standard regimens with approximately 70% of patients having relapse and metastasis after treatment. Consequently, identifying the mechanisms that drive HGSOC metastasis will translate into clinical managements that would improve their outcomes (1,(5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

“…Currently, significant efforts have been made for personalized treatment to improve prognosis of HGSOC patients, including application of genomic technologies to identify the expression profile, copy-number changes, mutations, and epigenetic modifications of the genes. RNA sequencing (RNA-seq) is one of the key genomic technologies applied to reveal molecular pathogenesis in HGSOC (5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

“…OC is a heterogeneous disease that is histologically classified into 5 major subtypes: high-grade serous, low-grade serous, clear cell carcinoma, endometrioid carcinoma, and mucinous ovarian carcinoma ( 3 , 4 ). High-grade serous ovarian cancer (HGSOC) is the most common histological subtype of OC and accounts for 67.5% of all OC subtypes ( 1 , 2 ), and remains the most lethal female cancer with an estimated 21,410 new cases and 13,770 deaths expected in the United States in 2021 ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive analysis of m6A-modified circRNAs in peritoneal metastasis of high grade serious carcinoma of ovary

Guo

Xu²,

Qiu³

et al. 2022

Front. Oncol.

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PurposeHigh-grade serous ovarian cancer (HGSOC) remains the most lethal female cancer due to metastasis. CircRNAs are recently identified to be modified by N6-methyladenosine (m6A) in many cells. However, the significance of m6A-modified circular RNAs (circRNAs) has not been elucidated in HGSOC peritoneal metastasis. Here, we aimed to investigate the participation and potential functions of m6A-modified circRNAs in HGSCO peritoneal metastasis.MethodsCancerous tissues were collected from the in situ and the peritoneal metastasis lesions of HGSCO patients. M6A-tagged circRNAs were identified by m6A-modified RNA immunoprecipitation sequencing (m6A-RIP-seq). Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to predict the potential functions of the m6A-modified circRNAs.ResultsFor the m6A-modified circRNAs, 259 were upregulated and 227 were downregulated in the peritoneal metastasis than in the situ lesions of HGSCO patients. For the m6A peaks, 1541 were upregulated and 1293 were downregulated in the peritoneal metastasis than in the in situ lesions of HGSCO patients. For the differential expressed circRNAs, 1911(19.6%) were upregulated and 2883(29.6%) were downregulated in the peritoneal metastasis than in the in situ lesions of HGSCO patients. The upregulated m6A-modified circRNAs were associated with the HIF-1 signaling. The downregulated m6A-modified circRNAs were associated with the MAPK signaling.ConclusionsThis work firstly identified the transcriptome-wide map of m6A-modified circRNAs in peritoneal metastasis of HGSCO. Our findings provided novel evidences about the participation of m6A-modified circRNAs via HIF-1 and MAPK signaling and a new insight in molecular target of HGSCO peritoneal metastasis.

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“…The integration of transcriptomics and metabolomics is considered an impactful approach for discovering potential biomarkers or key genes (Arend et al, 2022; Yang et al, 2022), increasingly applied in disease screening (Jha et al, 2015), and safety assessment (Kong, He, Liu, & Huang, 2022). Association analyses of gene expression profiles and metabolite profiles could provide a systematic understanding of toxic processes as well as mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomics and metabolomics reveal the role of CYP1A2 in psoralen/isopsoralen‐induced metabolic activation and hepatotoxicity

Zhang

Song

Zhao

et al. 2022

Phytotherapy Research

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Psoralen and isopsoralen are the pharmacologically important but hepatotoxic components in Psoraleae Fructus. The purpose of this study was to reveal the underlying mechanism of psoralen/isopsoralen‐induced hepatotoxicity. Initially, we applied integrated analyses of transcriptomic and metabolomic profiles in mice treated with psoralen and isopsoralen, highlighting the xenobiotic metabolism by cytochromes P450 as a potential pathway. Then, with verifications of expression levels by qRT‐PCR and western blot, affinities by molecular docking, and metabolic contributions by recombinant human CYP450 and mouse liver microsomes, CYP1A2 was screened out as the key metabolic enzyme. Afterwards, CYP1A2 induction and inhibition models in HepG2 cells and mice were established to verify the role of CYP1A2, demonstrating that induction of CYP1A2 aggravated the hepatotoxicity, and conversely inhibition alleviated the hepatotoxic effects. Additionally, we detected glutathione adducts with reactive intermediates of psoralen and isopsoralen generated by CYP1A2 metabolism in biosystems of recombinant human CYP1A2 and mouse liver microsomes, CYP1A2‐overexpressed HepG2 cells, mice livers and the chemical reaction system using UPLC‐Q‐TOF‐MS/MS. Ultimately, the high‐content screening presented the cellular oxidative stress and relevant hepatotoxicity due to glutathione depletion by reactive intermediates. In brief, our findings illustrated that CYP1A2‐mediated metabolic activation is responsible for the psoralen/isopsoralen‐induced hepatotoxicity.

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Metabolic Alterations and WNT Signaling Impact Immune Response in HGSOC

Cited by 11 publications

References 63 publications

Spatial transcriptomics reveals ovarian cancer subclones with distinct tumour microenvironments

Spatial transcriptomics reveals ovarian cancer subclones with distinct tumour microenvironments

Comprehensive analysis of m6A-modified circRNAs in peritoneal metastasis of high grade serious carcinoma of ovary

Transcriptomics and metabolomics reveal the role of CYP1A2 in psoralen/isopsoralen‐induced metabolic activation and hepatotoxicity

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