Itaconate and obesity-related hormones promote tumor progression – new insights on metabolic dysfunction in early-onset colon cancer
IntroductionObesity is a strong risk factor for early-onset colon cancer (EOCC) and is associated with chronic inflammation largely mediated by macrophages. The macrophage-specific metabolite itaconate promotes growth in several types of cancer; however, its role in colon cancer (CC) is unknown. Her...
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Frontiers Media S.A.
2025-06-01
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| author | Katharina M. Scheurlen Jacob Hallion Dylan L. Snook Anne MacLeod Robert J. Beal Mary A. Parks Andrew B. Littlefield Eliah Hiken Adrian T. Billeter Jeannette Bensen Jeremy T. Gaskins Julia Chariker Eric C. Rouchka Susan Galandiuk |
| author_facet | Katharina M. Scheurlen Jacob Hallion Dylan L. Snook Anne MacLeod Robert J. Beal Mary A. Parks Andrew B. Littlefield Eliah Hiken Adrian T. Billeter Jeannette Bensen Jeremy T. Gaskins Julia Chariker Eric C. Rouchka Susan Galandiuk |
| author_sort | Katharina M. Scheurlen |
| collection | DOAJ |
| description | IntroductionObesity is a strong risk factor for early-onset colon cancer (EOCC) and is associated with chronic inflammation largely mediated by macrophages. The macrophage-specific metabolite itaconate promotes growth in several types of cancer; however, its role in colon cancer (CC) is unknown. Here, we investigate a tumor promoting link between obesity-related hormones and itaconate within the NOTCH4-GATA4-IRG1 pathway in EOCC.MethodsPatient tissue (n=20) was obtained and qRT-PCR, ELISA, and mass spectrometry were performed to evaluate IRG1 expression (Human Immune-Responsive Gene 1, encoding ACOD1), ACOD1 expression (Cis-aconitate decarboxylase 1, enzyme producing itaconate), and itaconate concentration in human CC versus EOCC. RNA sequencing data from 5 sources in the USA and Europe were obtained to perform IRG1-related differential expression analysis (n=178), IRG1-related survival analysis (n=185), and differential expression analysis and survival analysis related to genes of the NOTCH4-GATA4-IRG1 pathway (n=371). Furthermore, tumor versus normal colon was compared and the interaction of tissue with sex, age, and body mass index (BMI) was investigated. A coculture model using two CC cell lines (HT-29 and SW480) and THP-1 cell line-derived M0 and M2-like macrophages was used to evaluate NOTCH4-GATA4-IRG1 pathway-related gene expression following treatment with obesity-related hormones (leptin, adiponectin) and itaconate derivatives.ResultsBoth ACOD1 and IRG1 expression were elevated in human CC tissue compared to adjacent normal colon tissue. Normal colon itaconate levels were higher in EOCC patients compared to that in older patients. Plasma itaconate levels in CC patients correlated with their BMI. Survival was decreased in IRG1-positive stage IV CC. IRG1-associated gene expression within the NOTCH4-GATA4-IRG1 pathway differed in CC versus normal colon tissue: GATA4, DLL4, VEGFA, and MAPK15 upregulation was associated with EOCC, while ABCG5 and GATA5 were downregulated in CCs and associated with higher BMI. Adiponectin and leptin treatment of macrophages cocultured with CC cells increased IRG1 expression.DiscussionObesity-related hormones can increase itaconate production in M2-like macrophages. IRG1 expression and the NOTCH4-GATA4-IRG1 pathway are associated with EOCC, BMI, and patient survival. As a macrophage metabolite affecting inflammation, itaconate may have a particular immunotherapeutic role in patients with EOCC. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-06-01 |
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| spelling | doaj-art-a1598ec3390445f882e071bf95660fdf2025-08-20T03:45:44ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-06-011610.3389/fimmu.2025.15729851572985Itaconate and obesity-related hormones promote tumor progression – new insights on metabolic dysfunction in early-onset colon cancerKatharina M. Scheurlen0Jacob Hallion1Dylan L. Snook2Anne MacLeod3Robert J. Beal4Mary A. Parks5Andrew B. Littlefield6Eliah Hiken7Adrian T. Billeter8Jeannette Bensen9Jeremy T. Gaskins10Julia Chariker11Eric C. Rouchka12Susan Galandiuk13Digestive Surgery Research Laboratory, Price Institute of Surgical Research, The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville, Louisville, KY, United StatesDigestive Surgery Research Laboratory, Price Institute of Surgical Research, The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville, Louisville, KY, United StatesDigestive Surgery Research Laboratory, Price Institute of Surgical Research, The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville, Louisville, KY, United StatesDigestive Surgery Research Laboratory, Price Institute of Surgical Research, The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville, Louisville, KY, United StatesDigestive Surgery Research Laboratory, Price Institute of Surgical Research, The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville, Louisville, KY, United StatesDigestive Surgery Research Laboratory, Price Institute of Surgical Research, The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville, Louisville, KY, United StatesDigestive Surgery Research Laboratory, Price Institute of Surgical Research, The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville, Louisville, KY, United StatesDigestive Surgery Research Laboratory, Price Institute of Surgical Research, The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville, Louisville, KY, United StatesDepartment of Visceral Surgery, Clarunis-University Digestive Healthcare Center, St. Claraspital and University Hospital Basel, Basel, SwitzerlandLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDepartment of Bioinformatics & Biostatistics, University of Louisville, Louisville, KY, United StatesKentucky IDeA Networks of Biomedical Research Excellence (KY INBRE), Bioinformatics Core, University of Louisville, Louisville, KY, United StatesKentucky IDeA Networks of Biomedical Research Excellence (KY INBRE), Bioinformatics Core, University of Louisville, Louisville, KY, United StatesDigestive Surgery Research Laboratory, Price Institute of Surgical Research, The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville, Louisville, KY, United StatesIntroductionObesity is a strong risk factor for early-onset colon cancer (EOCC) and is associated with chronic inflammation largely mediated by macrophages. The macrophage-specific metabolite itaconate promotes growth in several types of cancer; however, its role in colon cancer (CC) is unknown. Here, we investigate a tumor promoting link between obesity-related hormones and itaconate within the NOTCH4-GATA4-IRG1 pathway in EOCC.MethodsPatient tissue (n=20) was obtained and qRT-PCR, ELISA, and mass spectrometry were performed to evaluate IRG1 expression (Human Immune-Responsive Gene 1, encoding ACOD1), ACOD1 expression (Cis-aconitate decarboxylase 1, enzyme producing itaconate), and itaconate concentration in human CC versus EOCC. RNA sequencing data from 5 sources in the USA and Europe were obtained to perform IRG1-related differential expression analysis (n=178), IRG1-related survival analysis (n=185), and differential expression analysis and survival analysis related to genes of the NOTCH4-GATA4-IRG1 pathway (n=371). Furthermore, tumor versus normal colon was compared and the interaction of tissue with sex, age, and body mass index (BMI) was investigated. A coculture model using two CC cell lines (HT-29 and SW480) and THP-1 cell line-derived M0 and M2-like macrophages was used to evaluate NOTCH4-GATA4-IRG1 pathway-related gene expression following treatment with obesity-related hormones (leptin, adiponectin) and itaconate derivatives.ResultsBoth ACOD1 and IRG1 expression were elevated in human CC tissue compared to adjacent normal colon tissue. Normal colon itaconate levels were higher in EOCC patients compared to that in older patients. Plasma itaconate levels in CC patients correlated with their BMI. Survival was decreased in IRG1-positive stage IV CC. IRG1-associated gene expression within the NOTCH4-GATA4-IRG1 pathway differed in CC versus normal colon tissue: GATA4, DLL4, VEGFA, and MAPK15 upregulation was associated with EOCC, while ABCG5 and GATA5 were downregulated in CCs and associated with higher BMI. Adiponectin and leptin treatment of macrophages cocultured with CC cells increased IRG1 expression.DiscussionObesity-related hormones can increase itaconate production in M2-like macrophages. IRG1 expression and the NOTCH4-GATA4-IRG1 pathway are associated with EOCC, BMI, and patient survival. As a macrophage metabolite affecting inflammation, itaconate may have a particular immunotherapeutic role in patients with EOCC.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1572985/fullearly-onset colon cancermacrophagesimmunologyobesitymetabolism |
| spellingShingle | Katharina M. Scheurlen Jacob Hallion Dylan L. Snook Anne MacLeod Robert J. Beal Mary A. Parks Andrew B. Littlefield Eliah Hiken Adrian T. Billeter Jeannette Bensen Jeremy T. Gaskins Julia Chariker Eric C. Rouchka Susan Galandiuk Itaconate and obesity-related hormones promote tumor progression – new insights on metabolic dysfunction in early-onset colon cancer Frontiers in Immunology early-onset colon cancer macrophages immunology obesity metabolism |
| title | Itaconate and obesity-related hormones promote tumor progression – new insights on metabolic dysfunction in early-onset colon cancer |
| title_full | Itaconate and obesity-related hormones promote tumor progression – new insights on metabolic dysfunction in early-onset colon cancer |
| title_fullStr | Itaconate and obesity-related hormones promote tumor progression – new insights on metabolic dysfunction in early-onset colon cancer |
| title_full_unstemmed | Itaconate and obesity-related hormones promote tumor progression – new insights on metabolic dysfunction in early-onset colon cancer |
| title_short | Itaconate and obesity-related hormones promote tumor progression – new insights on metabolic dysfunction in early-onset colon cancer |
| title_sort | itaconate and obesity related hormones promote tumor progression new insights on metabolic dysfunction in early onset colon cancer |
| topic | early-onset colon cancer macrophages immunology obesity metabolism |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1572985/full |
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