Sex Differences in Colon Cancer Metabolism Reveal A Novel Subphenotype.
Ontology highlight
ABSTRACT:
SUBMITTER: Cai Y
PROVIDER: S-EPMC7078199 | biostudies-literature | 2020 Mar
REPOSITORIES: biostudies-literature
Publications
Sex Differences in Colon Cancer Metabolism Reveal A Novel Subphenotype.
Cai Yuping Y Rattray Nicholas J W NJW Zhang Qian Q Mironova Varvara V Santos-Neto Alvaro A Hsu Kuo-Shun KS Rattray Zahra Z Cross Justin R JR Zhang Yawei Y Paty Philip B PB Khan Sajid A SA Johnson Caroline H CH
Scientific reports 20200317 1
Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher incidence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes among all CRC patients. Aberrant metabolism is a known hallmark and therapeutic target for cancer. We propose that metabolic subphenotypes exist between CRCs due to intertumoral molecular and genomic variation, and differences in environmental milieu of the colon which vary between the ...[more]
Similar Datasets
Project description:<p>Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher prevalence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes amongst CRC patients. Aberrant metabolism is a feature of CRC, but it is not known if sex-differences exist. Metabolomics of patient colon tissues (n=236) revealed widespread sex-differences in metabolism depending on tumor location and stage. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production towards asparagine synthesis, and an increase in amino acid uptake. Gene expression data revealed an association between high asparagine synthase expression and poorer overall survival in women with CRC. This is the first study to show sex-differences in tumor tissue metabolism for CRC patients revealing a nutrient-deplete subtype in women with RCC. The results therefore have implications for tumor progression and therapeutic response in women with RCC.</p><p><br></p><p>Linked Studies:</p><p>UPLC-MS HILIC POS assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1122" target="_blank">MTBLS1122</a></p><p>UPLC-MS HILIC NEG assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1124" target="_blank">MTBLS1124</a></p><p>UPLC-MS RP POS assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1129" target="_blank">MTBLS1129</a></p><p>UPLC-MS RP NEG assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1130" target="_blank">MTBLS1130</a></p>
2020-08-01 | MSV000085877 | GNPS
Project description:<p>Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher prevalence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes amongst CRC patients. Aberrant metabolism is a feature of CRC, but it is not known if sex-differences exist. Metabolomics of patient colon tissues (n=236) revealed widespread sex-differences in metabolism depending on tumor location and stage. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production towards asparagine synthesis, and an increase in amino acid uptake. Gene expression data revealed an association between high asparagine synthase expression and poorer overall survival in women with CRC. This is the first study to show sex-differences in tumor tissue metabolism for CRC patients revealing a nutrient-deplete subtype in women with RCC. The results therefore have implications for tumor progression and therapeutic response in women with RCC.</p><p><br></p><p>Linked Studies:</p><p>UPLC-MS HILIC POS assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1122" target="_blank">MTBLS1122</a></p><p>UPLC-MS HILIC NEG assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1124" target="_blank">MTBLS1124</a></p><p>UPLC-MS RP POS assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1129" target="_blank">MTBLS1129</a></p><p>UPLC-MS RP NEG assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1130" target="_blank">MTBLS1130</a></p>
2020-08-01 | MSV000085874 | GNPS
Project description:<p>Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher prevalence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes amongst CRC patients. Aberrant metabolism is a feature of CRC, but it is not known if sex-differences exist. Metabolomics of patient colon tissues (n=236) revealed widespread sex-differences in metabolism depending on tumor location and stage. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production towards asparagine synthesis, and an increase in amino acid uptake. Gene expression data revealed an association between high asparagine synthase expression and poorer overall survival in women with CRC. This is the first study to show sex-differences in tumor tissue metabolism for CRC patients revealing a nutrient-deplete subtype in women with RCC. The results therefore have implications for tumor progression and therapeutic response in women with RCC.</p><p><br></p><p>Linked Studies:</p><p>UPLC-MS HILIC POS assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1122" target="_blank">MTBLS1122</a></p><p>UPLC-MS HILIC NEG assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1124" target="_blank">MTBLS1124</a></p><p>UPLC-MS RP POS assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1129" target="_blank">MTBLS1129</a></p><p>UPLC-MS RP NEG assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1130" target="_blank">MTBLS1130</a></p>
2020-08-01 | MSV000085889 | GNPS
Project description:<p>Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher prevalence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes amongst CRC patients. Aberrant metabolism is a feature of CRC, but it is not known if sex-differences exist. Metabolomics of patient colon tissues (n=236) revealed widespread sex-differences in metabolism depending on tumor location and stage. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production towards asparagine synthesis, and an increase in amino acid uptake. Gene expression data revealed an association between high asparagine synthase expression and poorer overall survival in women with CRC. This is the first study to show sex-differences in tumor tissue metabolism for CRC patients revealing a nutrient-deplete subtype in women with RCC. The results therefore have implications for tumor progression and therapeutic response in women with RCC.</p><p><br></p><p>Linked Studies:</p><p>UPLC-MS HILIC POS assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1122" target="_blank">MTBLS1122</a></p><p>UPLC-MS HILIC NEG assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1124" target="_blank">MTBLS1124</a></p><p>UPLC-MS RP POS assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1129" target="_blank">MTBLS1129</a></p><p>UPLC-MS RP NEG assay is reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS1130" target="_blank">MTBLS1130</a></p>
2020-08-01 | MSV000085884 | GNPS
Project description:<p>Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher incidence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes among all CRC patients. Aberrant metabolism is a known hallmark and therapeutic target for cancer. We propose that metabolic subphenotypes exist between CRCs due to intertumoral molecular and genomic variation, and differences in environmental milieu of the colon which vary between the sexes. Metabolomics analysis of patient colon tumors (n = 197) and normal tissues (n = 39) revealed sex-specific metabolic subphenotypes dependent on anatomic location. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production to fuel asparagine synthesis and amino acid uptake. The clinical importance of our findings were further investigated in an independent data set from The Cancer Genomic Atlas, and demonstrated that high asparagine synthetase (ASNS) expression correlated with poorer survival for women. This is the first study to show a unique, nutrient-deplete metabolic subphenotype in women with RCC, with implications for tumor progression and outcomes in CRC patients.</p><p><br></p><p><strong>UPLC-MS HILIC POS assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1122' rel='noopener noreferrer' target='_blank'><strong>MTBLS1122</strong></a>.</p><p><strong>UPLC-MS HILIC NEG assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1124' rel='noopener noreferrer' target='_blank'><strong>MTBLS1124</strong></a>.</p><p><strong>UPLC-MS RP POS assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1129' rel='noopener noreferrer' target='_blank'><strong>MTBLS1129</strong></a>.</p><p><strong>UPLC-MS RP NEG assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1130' rel='noopener noreferrer' target='_blank'><strong>MTBLS1130</strong></a>.</p>
2020-03-19 | MTBLS1124 | MetaboLights
Project description:<p>Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher incidence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes among all CRC patients. Aberrant metabolism is a known hallmark and therapeutic target for cancer. We propose that metabolic subphenotypes exist between CRCs due to intertumoral molecular and genomic variation, and differences in environmental milieu of the colon which vary between the sexes. Metabolomics analysis of patient colon tumors (n = 197) and normal tissues (n = 39) revealed sex-specific metabolic subphenotypes dependent on anatomic location. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production to fuel asparagine synthesis and amino acid uptake. The clinical importance of our findings were further investigated in an independent data set from The Cancer Genomic Atlas, and demonstrated that high asparagine synthetase (ASNS) expression correlated with poorer survival for women. This is the first study to show a unique, nutrient-deplete metabolic subphenotype in women with RCC, with implications for tumor progression and outcomes in CRC patients.</p><p><br></p><p><strong>UPLC-MS HILIC POS assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1122' rel='noopener noreferrer' target='_blank'><strong>MTBLS1122</strong></a>.</p><p><strong>UPLC-MS HILIC NEG assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1124' rel='noopener noreferrer' target='_blank'><strong>MTBLS1124</strong></a>.</p><p><strong>UPLC-MS RP POS assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1129' rel='noopener noreferrer' target='_blank'><strong>MTBLS1129</strong></a>.</p><p><strong>UPLC-MS RP NEG assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1130' rel='noopener noreferrer' target='_blank'><strong>MTBLS1130</strong></a>.</p>
2020-03-19 | MTBLS1130 | MetaboLights
Project description:<p>Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher incidence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes among all CRC patients. Aberrant metabolism is a known hallmark and therapeutic target for cancer. We propose that metabolic subphenotypes exist between CRCs due to intertumoral molecular and genomic variation, and differences in environmental milieu of the colon which vary between the sexes. Metabolomics analysis of patient colon tumors (n = 197) and normal tissues (n = 39) revealed sex-specific metabolic subphenotypes dependent on anatomic location. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production to fuel asparagine synthesis and amino acid uptake. The clinical importance of our findings were further investigated in an independent data set from The Cancer Genomic Atlas, and demonstrated that high asparagine synthetase (ASNS) expression correlated with poorer survival for women. This is the first study to show a unique, nutrient-deplete metabolic subphenotype in women with RCC, with implications for tumor progression and outcomes in CRC patients.</p><p><br></p><p><strong>UPLC-MS HILIC POS assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1122' rel='noopener noreferrer' target='_blank'><strong>MTBLS1122</strong></a>.</p><p><strong>UPLC-MS HILIC NEG assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1124' rel='noopener noreferrer' target='_blank'><strong>MTBLS1124</strong></a>.</p><p><strong>UPLC-MS RP POS assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1129' rel='noopener noreferrer' target='_blank'><strong>MTBLS1129</strong></a>.</p><p><strong>UPLC-MS RP NEG assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1130' rel='noopener noreferrer' target='_blank'><strong>MTBLS1130</strong></a>.</p>
2020-03-19 | MTBLS1129 | MetaboLights
Project description:<p>Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher incidence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes among all CRC patients. Aberrant metabolism is a known hallmark and therapeutic target for cancer. We propose that metabolic subphenotypes exist between CRCs due to intertumoral molecular and genomic variation, and differences in environmental milieu of the colon which vary between the sexes. Metabolomics analysis of patient colon tumors (n = 197) and normal tissues (n = 39) revealed sex-specific metabolic subphenotypes dependent on anatomic location. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production to fuel asparagine synthesis and amino acid uptake. The clinical importance of our findings were further investigated in an independent data set from The Cancer Genomic Atlas, and demonstrated that high asparagine synthetase (ASNS) expression correlated with poorer survival for women. This is the first study to show a unique, nutrient-deplete metabolic subphenotype in women with RCC, with implications for tumor progression and outcomes in CRC patients.</p><p><br></p><p><strong>UPLC-MS HILIC POS assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1122' rel='noopener noreferrer' target='_blank'><strong>MTBLS1122</strong></a>.</p><p><strong>UPLC-MS HILIC NEG assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1124' rel='noopener noreferrer' target='_blank'><strong>MTBLS1124</strong></a>.</p><p><strong>UPLC-MS RP POS assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1129' rel='noopener noreferrer' target='_blank'><strong>MTBLS1129</strong></a>.</p><p><strong>UPLC-MS RP NEG assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1130' rel='noopener noreferrer' target='_blank'><strong>MTBLS1130</strong></a>.</p>
2020-03-19 | MTBLS1122 | MetaboLights
Project description:Understanding sex differences in colon cancer is essential to advance disease prevention, diagnosis, and treatment. Males have a higher risk of developing colon cancer and a lower survival rate than women. However, the molecular features that drive these sex differences are poorly understood. In this study, we use both transcript-based and gene regulatory network methods to analyze RNA-seq data from The Cancer Genome Atlas for 445 patients with colon cancer. We compared gene expression between tumors in men and women and observed significant sex differences in sex chromosome genes only. We then inferred patient-specific gene regulatory networks and found significant regulatory differences between males and females, with drug and xenobiotics metabolism via cytochrome P450 pathways more strongly targeted in females. This finding was validated in a dataset of 1,193 patients from five independent studies. While targeting, the drug metabolism pathway did not change overall survival for males treated with adjuvant chemotherapy, females with greater targeting showed an increase in 10-year overall survival probability, 89% [95% confidence interval (CI), 78-100] survival compared with 61% (95% CI, 45-82) for women with lower targeting, respectively (P = 0.034). Our network analysis uncovers patterns of transcriptional regulation that differentiate male and female colon cancer and identifies differences in regulatory processes involving the drug metabolism pathway associated with survival in women who receive adjuvant chemotherapy. This approach can be used to investigate the molecular features that drive sex differences in other cancers and complex diseases.Significance: A network-based approach reveals that sex-specific patterns of gene targeting by transcriptional regulators are associated with survival outcome in colon cancer. This approach can be used to understand how sex influences progression and response to therapies in other cancers. Cancer Res; 78(19); 5538-47. ©2018 AACR.
| S-EPMC6169995 | biostudies-literature
Project description:BackgroundBrain cancer incidence and mortality rates are greater in males. Understanding the molecular mechanisms that underlie those sex differences could improve treatment strategies. Although sex differences in normal metabolism are well described, it is currently unknown whether they persist in cancerous tissue.MethodsUsing positron emission tomography (PET) imaging and mass spectrometry, we assessed sex differences in glioma metabolism in samples from affected individuals. We assessed the role of glutamine metabolism in male and female murine transformed astrocytes using isotope labeling, metabolic rescue experiments, and pharmacological and genetic perturbations to modulate pathway activity.FindingsWe found that male glioblastoma surgical specimens are enriched for amino acid metabolites, including glutamine. Fluoroglutamine PET imaging analyses showed that gliomas in affected male individuals exhibit significantly higher glutamine uptake. These sex differences were well modeled in murine transformed astrocytes, in which male cells imported and metabolized more glutamine and were more sensitive to glutaminase 1 (GLS1) inhibition. The sensitivity to GLS1 inhibition in males was driven by their dependence on glutamine-derived glutamate for α-ketoglutarate synthesis and tricarboxylic acid (TCA) cycle replenishment. Females were resistant to GLS1 inhibition through greater pyruvate carboxylase (PC)-mediated TCA cycle replenishment, and knockdown of PC sensitized females to GLS1 inhibition.ConclusionOur results show that clinically important sex differences exist in targetable elements of metabolism. Recognition of sex-biased metabolism may improve treatments through further laboratory and clinical research.FundingThis work was supported by NIH grants, Joshua's Great Things, the Siteman Investment Program, and the Barnard Research Fund.
| S-EPMC9669217 | biostudies-literature