Integrative analysis deciphers the heterogeneity of cancer-associated fibroblast and implications on clinical outcomes in ovarian cancers.
Name:
Publisher version
Date
2022-11-14Journal
Computational and structural biotechnology journalType
ArticleMetadata
Show full item recordAbstract
Accumulating evidence has recognized that cancer-associated fibroblasts (CAFs) are major players in the desmoplastic stroma of ovarian cancer, modulating tumor progression and therapeutic response. However, it is unclear regarding the signatures of CAFs could be utilized to predict the clinical outcomes of ovarian cancer patients. To fill in this gap, we explored the intratumoral compartment of ovarian cancer by analyzing the single-cell RNA-sequencing (scRNA-seq) datasets of ovarian carcinoma samples, and identified two distinct CAFs (tumor-promoting CAF_c1 subtype and myofibroblasts-like CAF_c2 subtype). The clinical significance of CAF subtypes was further validated in The Cancer Genomics Atlas (TCGA) database and other independent immunotherapy response datasets, and the results revealed that the patients with a higher expression of CAF_c1 signatures had a worse prognosis and showed a tendency of resistance to immunotherapy. This work uncovered the signatures of the CAF_c1 subtype that could serve as a novel prognostic indicator and predictive marker for immunotherapy.Rights/Terms
© 2022 The Author(s).Keyword
BRCA, Breast invasive carcinomaBio-marker
CAFs
CAFs, Cancer-associated fibroblasts
COAD, Colon adenocarcinoma
ESCA, Esophageal carcinoma
Gene signature
HGSOC, High-grade serous ovarian carcinoma
HNSC, Head and neck squamous cell carcinoma
ImmunotherapyLUAD, Lung adenocarcinomaLUSC, Lung squamous cell carcinomaOV, Ovarian serous cystadenocarcinomaOvarian cancerPrognosisSKCM, Skin cutaneous melanomaSingle-cell sequencingTCGA, The Cancer Genomics AtlasTHCA, Thyroid cancerUCEC, Uterine corpus endometrial carcinomascRNA-seq, Single-cell RNA-sequencing
Identifier to cite or link to this item
http://hdl.handle.net/10713/20257Scopus Count
Collections
Related items
Showing items related by title, author, creator and subject.
-
Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma.Hepatocellular carcinoma (HCC) incidence, as well as related mortality, has been steadily increasing in the USA and across the globe, partly due to the lack of effective therapeutic options for advanced HCC. Though sorafenib is considered standard-of-care for advanced HCC, it only improves median survival by a few months when compared to placebo. Sorafenib is also associated with several unpleasant side effects that often lead to early abatement of therapy. Here, we investigate whether a combination regimen including low-dose sorafenib and a non-toxic dose of anti-diabetic drug metformin can achieve effective inhibition of HCC. Indeed, combining metformin with low-dose sorafenib inhibited growth, proliferation, migration, and invasion potential of HCC cells. We observed a 5.3- and 1.9-fold increase in sub-G1 population in the combination treatment compared to sorafenib alone. We found that the combination of metformin enhanced the efficacy of sorafenib and inhibited the MAPK/ERK/Stat3 axis. Our in vivo studies corroborated the in vitro findings, and mice harboring HepG2-derived tumors showed effective tumor reduction upon treatment with low-dose sorafenib and metformin combination. This work sheds light on a therapeutic strategy aiming to augment sorafenib efficacy or dose-de-escalation that may prove beneficial in circumventing sorafenib resistance as well as minimizing related side effects.
-
Microbiome composition and effects in tumors, with a focus on gastric carcinomasAn estimated 15-20% of cancers worldwide are linked to viral, parasitic, or bacterial infections, and in 2008 these cases were responsible for 1.5 million cancer deaths worldwide. The best-studied examples of microbes contributing to cancer are hepatitis B virus, human papillomavirus, Epstein-Barr virus, human immunodeficiency virus, Schistosoma haematobium and Helicobacter pylori. Of these, H. pylori is the only bacteria considered to be a definite carcinogen. These microbes are primarily known to contribute to cancerous mutations through chronic inflammation. We hypothesized that other bacteria may also influence carcinogenesis through inflammation and other mechanisms. We sought to use the latest sequencing techniques and publicly available sequence data to identify novel bacteria in tumors and to further our understanding of the relationship between H. pylori and the gastric epithelium with a dual-species transcriptomics approach. During this process, sequence alignment techniques were optimized and are described here as best practices. Our analysis of publicly available cancer data led to the conclusion that Pseudomonas spp. and Acinetobacter spp. may be biologically relevant in gastric cancer samples and acute myeloid leukemia samples, respectively. Some bacterial species were found to be contaminant bacteria in each cancer type studied, while Mycobacterium spp. was identified as a contaminant in only the ovarian cancer samples sequenced at The Broad Institute. In our examination of H. pylori, the only known definite carcinogen, we identified differences in inflammatory pathways between tumor and adjacent samples both colonized with H. pylori. A co- transcriptomics approach was then used to determine the gastric epithelial response to H. pylori 26695 with and without cagE, a necessary gene for the type IV secretion system and secretion of the oncoprotein CagA. Multiple inflammatory pathways were activated in response to the H. pylori 26695 cagE+ compared to the cagE- strain. The bacterial response to the switch from broth to co-culture was also studied and both strains were determined to activate oipA and urease genes in response to gastric epithelial cells. Collectively, these findings advance our understanding of bacteria and their relationship to cancer.
-
Determinants of Improved Survival in Patients with Hepatocellular Carcinoma: A SEER-Medicare AnalysisBackground: Curative treatment of hepatocellular carcinoma (HCC) improves 5-year survival rates from 0-5% to 40-70%.1, 2 We aimed to study the: I) effect of routine non-HCC cancer screening tests (nHCS) on earlier cancer detection and survival; and II) impact of receiving recommended HCC treatment per the American Association for the Study of Liver Diseases guidelines, on adverse events (AE) and survival versus non-recommended therapies. Methods: This retrospective cohort study evaluates Medicare beneficiaries with HCC from 2004-2007 using SEER-Medicare registry. Outcomes ( Aim I) were stage at diagnosis (American Joint Commission on Cancer) dichotomized into non-late (Stages I-III) and late stage HCC (Stage IV); and mortality. The odds of late stage at diagnosis and hazard of death among >67 year old recipients of nHCS within 2 years before HCC diagnosis were determined by logistic and Cox proportional hazards regression, respectively, stratified by sex and adjusted for sociodemographic variables, year of diagnosis, HCC risk factors, and comorbidities. For Aim II, patients >66 years were stratified according to stage at diagnosis, tumor size/nodularity, and cirrhosis. Within each group, AE operationalized as non-treatment hospitalizations, and mortality, were compared among those receiving and not receiving recommended treatments. Risk of hospitalization and death (binary variables) within each person-day were explored via logistic regression and generalized estimating equations (correcting for correlation in hospitalization days). Results: Women receiving nHCS (Aim I) in the 2 years before HCC had higher odds of non-late after adjustment. An analysis dichotomizing stages into Early (I/II) and Late (III/IV) found no difference between the two groups. Men and women receiving nHCS had reduced mortality, independent of stage at diagnosis. (Aim II) There were higher hospitalization and lower mortality among Stages I/II patients receiving recommended versus non-recommended therapy; and the opposite effect in Stages III/IV. Conclusions: Medicare recipients receiving nHCS had reduced mortality, independent of earlier diagnosis, suggesting a need to follow routine cancer screening guidelines among HCC patients. Those receiving guideline-recommended therapy had reduced mortality but increased hospitalization in Stages I/II; with the opposite effect among Stages III/IV, suggesting that treating HCC patients according to guidelines improves survival, despite the cost of hospitalizations.
