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Grant Details

Grant Number: 5U01CA272529-02 Interpret this number
Primary Investigator: Playdon, Mary
Organization: University Of Utah
Project Title: Ceramides as Novel Drivers of Metabolic Dysfunction and Colorectal Cancer
Fiscal Year: 2023


Abstract

SUMMARY In response to the burgeoning worldwide obesity pandemic, the rate of obesity-associated colorectal cancer (CRC) remains an enormous public health burden. The metabolic determinants of CRC are complex and remain under debate. Ceramides are pathogenic lipids that signal a state of nutrition excess and accumulate in organs that are not suited for fat storage, driving insulin resistance and dyslipidemia. Our preliminary data also demonstrate that ceramides are critical intermediates linking nutritional inputs like fatty acids to intestinal stem cell proliferation. Our long-term goal is to understand the role of ceramide metabolism in the development of CRC and to identify pharmacologic and dietary strategies to intervene upon ceramide metabolism for cancer prevention. Our central hypothesis is that ceramide metabolism is a key component of metabolic dysregulation underlying CRC. We propose a transdisciplinary collaboration, utilizing epidemiologic and clinical cohorts and animal experiments, to conduct synergistic analyses and interventions to address our hypothesis. In Aim 1a, using a rigorous discovery-replication design, we will characterize a ceramide-based CRC risk score in serum from participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) (n=1260cases/1260 controls), and the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer cohort (n=1234 cases/1234 controls), and identify a dietary pattern strongly linked to ceramides. In Aim 1b, we will determine the effects of medical and surgical weight loss and changes in body composition on the ceramide CRC risk score in our ongoing Utah Bariatric Surgery Cohort. In Aim 1c, we will measure the association of genetically predicted levels of circulating ceramides with risk of CRC using data from 57,873 CRC cases and 67,087 controls in the Genetics and Epidemiology of CRC Consortium (GECCO), and test for gene by dietary pattern interaction. In Aim 2, we will determine whether systemic or tissue-specific reduction of ceramides affects CRC development. We will impede ceramide synthesis by inhibiting dihydroceramide desaturase-1 (DES1) action genetically (Aim 2a) and pharmacologically (Aim 2b), and via a serine or time restricted dietary pattern (Aim 2c), to test for effects on gut, liver and adipose depots and colorectal tumor incidence in an azoxymethane mouse model of CRC. The study leverages a new class of DES1 inhibitors that lower tissue ceramides and ameliorate the pathogenic consequences of obesity. The proposed study fills a major gap in evidence for understanding how ceramides contribute to the metabolic dysregulation underlying CRC. We propose a fully translational approach integrating epidemiologic associations between ceramides and colorectal malignancies and preclinical studies testing the utility of ceramide-lowering interventions on cancer endpoints. Findings will have important implications for understanding the biologic mechanisms underpinning obesity-associated metabolic dysregulation in CRC and for identifying new targets for CRC prevention.



Publications

Ceramides are Fuel Gauges on the Drive to Cardiometabolic Disease.
Authors: Wilkerson J.L. , Tatum S.M. , Holland W.L. , Summers S.A. .
Source: Physiological reviews, 2024-02-01; , .
EPub date: 2024-02-01.
PMID: 38300524
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Ceramides Increase Fatty Acid Utilization in Intestinal Progenitors to Enhance Stemness and Increase Tumor Risk.
Authors: Li Y. , Chaurasia B. , Rahman M.M. , Kaddai V. , Maschek J.A. , Berg J.A. , Wilkerson J.L. , Mahmassani Z.S. , Cox J. , Wei P. , et al. .
Source: Gastroenterology, 2023 Nov; 165(5), p. 1136-1150.
EPub date: 2023-08-02.
PMID: 37541526
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Ramadan intermittent fasting is associated with ameliorated inflammatory markers and improved plasma sphingolipids/ceramides in subjects with obesity: lipidomics analysis.
Authors: Madkour M.I. , Islam M.T. , Tippetts T.S. , Chowdhury K.H. , Lesniewski L.A. , Summers S.A. , Zeb F. , Abdelrahim D.N. , AlKurd R. , Khraiwesh H.M. , et al. .
Source: Scientific reports, 2023-10-13; 13(1), p. 17322.
EPub date: 2023-10-13.
PMID: 37833312
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New-Onset Diabetes after an Obesity-Related Cancer Diagnosis and Survival Outcomes in the Women's Health Initiative.
Authors: Karra P. , Hardikar S. , Winn M. , Anderson G.L. , Haaland B. , Krick B. , Thomson C.A. , Shadyab A. , Luo J. , Saquib N. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2023-10-02; 32(10), p. 1356-1364.
PMID: 37590895
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Vitamin B2 enables regulation of fasting glucose availability.
Authors: Masschelin P.M. , Saha P. , Ochsner S.A. , Cox A.R. , Kim K.H. , Felix J.B. , Sharp R. , Li X. , Tan L. , Park J.H. , et al. .
Source: eLife, 2023-07-07; 12, .
EPub date: 2023-07-07.
PMID: 37417957
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Placing a Hex on Glucose Uptake.
Authors: Bowman F.M. , Summers S.A. , Holland W.L. .
Source: Diabetes, 2023-06-01; 72(6), p. 690-692.
PMID: 37205863
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Metabolic and bariatric surgery and obesity pharmacotherapy for cancer prevention: current status and future possibilities.
Authors: Playdon M.C. , Hardikar S. , Karra P. , Hoobler R. , Ibele A.R. , Cook K.L. , Kumar A. , Ippolito J.E. , Brown J.C. .
Source: Journal of the National Cancer Institute. Monographs, 2023-05-04; 2023(61), p. 68-76.
PMID: 37139980
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Writing and erasing ceramides to alter liver disease.
Authors: Weber-Stout M. , Summers S.A. , Holland W.L. .
Source: Nature metabolism, 2023 May; 5(5), p. 727-729.
PMID: 37188817
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Associations of combined physical activity and body mass index groups with colorectal cancer survival outcomes.
Authors: Himbert C. , Ose J. , Gigic B. , Viskochil R. , Santuci K. , Lin T. , Ashworth A. , Cohan J.N. , Scaife C.L. , Jedrzkiewicz J. , et al. .
Source: BMC cancer, 2023-04-03; 23(1), p. 300.
EPub date: 2023-04-03.
PMID: 37013476
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Inflammatory and insulinemic dietary patterns and risk of endometrial cancer among US women.
Authors: Romanos-Nanclares A. , Tabung F.K. , Sinnott J.A. , Trabert B. , De Vivo I. , Playdon M.C. , Eliassen A.H. .
Source: Journal of the National Cancer Institute, 2023-03-09; 115(3), p. 311-321.
PMID: 36515492
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Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study.
Authors: Papadimitriou N. , Bull C.J. , Jenab M. , Hughes D.J. , Bell J.A. , Sanderson E. , Timpson N.J. , Smith G.D. , Albanes D. , Campbell P.T. , et al. .
Source: BMC medicine, 2023-01-04; 21(1), p. 5.
EPub date: 2023-01-04.
PMID: 36600297
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Sociocultural influences on dietary behavior and meal timing among Native Hawaiian and Pacific Islander women at risk of endometrial cancer: a qualitative investigation.
Authors: Playdon M. , Rogers T.N. , Brooks E. , Petersen E.M. , Tavake-Pasi F. , Lopez J.A. , Quintana X. , Aitaoto N. , Rogers C.R. .
Source: Cancer causes & control : CCC, 2023 Jan; 34(1), p. 23-37.
EPub date: 2022-10-08.
PMID: 36208351
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Metabolic dysfunction and obesity-related cancer: Results from the cross-sectional National Health and Nutrition Examination Survey.
Authors: Winn M. , Karra P. , Haaland B. , Doherty J.A. , Summers S.A. , Litchman M.L. , Gunter M.J. , Playdon M.C. , Hardikar S. .
Source: Cancer medicine, 2023 Jan; 12(1), p. 606-618.
EPub date: 2022-06-19.
PMID: 35719035
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Associations of Individual and Combined Physical Activity and Body Mass Index Groups with Proinflammatory Biomarkers among Colorectal Cancer Patients.
Authors: Himbert C. , Warby C.A. , Gigic B. , Ose J. , Lin T. , Viskochil R. , Peoples A.R. , Ashworth A. , Schrotz-King P. , Scaife C.L. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2022-12-05; 31(12), p. 2148-2156.
PMID: 36099423
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The Use of Ceramides to Predict Metabolic Response to Metformin in Women With PCOS.
Authors: Sharma A. , Krick B. , Li Y. , Summers S.A. , Playdon M.C. , Welt C. .
Source: Journal of the Endocrine Society, 2022-10-11; 6(11), p. bvac131.
EPub date: 2022-09-02.
PMID: 36249411
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Ceramides and Acute Kidney Injury.
Authors: Nicholson R.J. , Holland W.L. , Summers S.A. .
Source: Seminars in nephrology, 2022 May; 42(3), p. 151281.
EPub date: 2022-11-18.
PMID: 36404212
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Differences in the gut microbiome by physical activity and BMI among colorectal cancer patients.
Authors: Himbert C. , Stephens W.Z. , Gigic B. , Hardikar S. , Holowatyj A.N. , Lin T. , Ose J. , Swanson E. , Ashworth A. , Warby C.A. , et al. .
Source: American journal of cancer research, 2022; 12(10), p. 4789-4801.
EPub date: 2022-10-15.
PMID: 36381318
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