Program Official

Principal Investigator

Cornelia M
Ulrich
Awardee Organization

University Of Utah
United States

Fiscal Year
2023
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Adipose tissue-colorectal tumor cross-talk: new targets for breaking the obesity-cancer link

The pandemic rise of obesity worldwide is alarming, with the highest increases occurring in the United States. Obesity is a major risk factor for many cancer types, including colon cancer (CC). To date, the biologic mechanisms underlying this relationship, specifically the potential signaling between dysregulated adipose tissue and adjacent tumor, are incompletely understood. Given the rising rates of obesity and the challenges for many people to lose excess adipose tissue, an integrated, multilevel approach to efficiently identify crosstalk and validate key molecular targets is needed to develop effective mechanism-based strategies for prevention and control of obesity-driven CC. We hypothesize that the metabolic and inflammatory perturbations induced by obesity increase CC risk through altered signaling between adipocytes and colon epithelial/tumor cells, and that inhibition of this crosstalk will disrupt the obesity-CC link. We will test this hypothesis through the integration of: 1) a unique, prospective, multicenter epidemiologic cohort of normoweight to obese CC patients, from whom paired serum, tumor, and tumor-adjacent adipose tissue samples will be used to discover and validate lead targets; and 2) complementary in vivo models of lean and diet-induced obese mice with CC, together with in vitro/in vivo organoid models in which potential targets underlying the effects of obesity on CC will be tested mechanistically. This unique transdisciplinary approach utilizes innovative clinical/epidemiological and preclinical studies of biochemical, transcriptomic, and metabolomics analyses in rigorous study designs to identify and validate new targets for disrupting the reciprocal crosstalk between adipocytes and colonic epithelial cells. We propose three synergistic aims: 1a) to discover and validate targets underlying the adipose tissue-CC link, using 400 CC patients; b) to identify and validate metabolic and transcriptomic signatures of adipocyte-colonocyte crosstalk; 2) to characterize the adipocyte-colonocyte crosstalk underlying the obesity-CC link, using two rigorous mouse models of CC; 3) to determine the causal role of candidate epithelial target genes in obesity-associated CC progression using murine in vitro and in vivo organoid CC models. This paradigm-shifting transdisciplinary collaboration builds on extensive preliminary data and generates maximum synergy through complementary human and murine studies, using identical state-of-the-art biomarker panels and platforms across clinical and preclinical studies. We anticipate that findings from these proposed studies will address the clinical challenges associated with obesity and CC by establishing causal links of the most promising targets for intercepting and disrupting adipocyte-epithelial cell crosstalk.

Publications

  • Oswald LB, Bloomer A, Li X, Jean-Baptiste E, Trujillo G, Felder S, Small BJ, Ose J, Hardikar S, Strehli I, Huang LC, Mooney K, Mutch MG, Chao D, Cohen SA, Karchi M, Wood EH, Damerell V, Loroña NC, Gong J, Toriola AT, Li CI, Shibata D, Schneider M, Gigic B, Figueiredo JC, Jim HSL, Ulrich CM, Siegel EM. Functional quality of life among newly diagnosed young adult colorectal cancer survivors compared to older adults: results from the ColoCare Study. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2024 Apr 19;32(5):298. PMID: 38639810
  • Himbert C, Ose J, Gigic B, Viskochil R, Santuci K, Lin T, Ashworth A, Cohan JN, Scaife CL, Jedrzkiewicz J, Damerell V, Atkins KM, Gong J, Mutch MG, Bernadt C, Felder S, Sanchez J, Cohen SA, Krane MK, Hinkle N, Wood E, Peoples AR, Figueiredo JC, Toriola AT, Siegel EM, Li CI, Shibata D, Boucher K, Round JL, Ulrich AB, Schneider M, Huang LC, Hardikar S, Ulrich CM. Associations of combined physical activity and body mass index groups with colorectal cancer survival outcomes. BMC cancer. 2023 Apr 3;23(1):300. PMID: 37013476
  • Himbert C, Stephens WZ, Gigic B, Hardikar S, Holowatyj AN, Lin T, Ose J, Swanson E, Ashworth A, Warby CA, Peoples AR, Nix D, Jedrzkiewicz J, Bronner M, Pickron B, Scaife C, Cohan JN, Schrotz-King P, Habermann N, Boehm J, Hullar M, Figueiredo JC, Toriola AT, Siegel EM, Li CI, Ulrich AB, Shibata D, Boucher K, Huang LC, Schneider M, Round JL, Ulrich CM. Differences in the gut microbiome by physical activity and BMI among colorectal cancer patients. American journal of cancer research. 2022 Oct 15;12(10):4789-4801. eCollection 2022. PMID: 36381318
  • Lindley CL, Gigic B, Peoples AR, Han CJ, Lin T, Himbert C, Warby CA, Boehm J, Hardikar S, Ashworth A, Schneider M, Ulrich A, Schrotz-King P, Figueiredo JC, Li CI, Shibata D, Siegel EM, Toriola AT, Ulrich CM, Syrjala KL, Ose J. Pre-Surgery Inflammatory and Angiogenesis Biomarkers as Predictors of 12-Month Cancer-Related Distress: Results from the ColoCare Study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2023 Mar 6;32(3):363-370. PMID: 36595657
  • Bowers LW, Glenny EM, Punjala A, Lanman NA, Goldbaum A, Himbert C, Montgomery SA, Yang P, Roper J, Ulrich CM, Dannenberg AJ, Coleman MF, Hursting SD. Weight Loss and/or Sulindac Mitigate Obesity-associated Transcriptome, Microbiome, and Protumor Effects in a Murine Model of Colon Cancer. Cancer prevention research (Philadelphia, Pa.). 2022 Aug 1;15(8):481-495. PMID: 35653548
  • Shu X, Chen Z, Long J, Guo X, Yang Y, Qu C, Ahn YO, Cai Q, Casey G, Gruber SB, Huyghe JR, Jee SH, Jenkins MA, Jia WH, Jung KJ, Kamatani Y, Kim DH, Kim J, Kweon SS, Le Marchand L, Matsuda K, Matsuo K, Newcomb PA, Oh JH, Ose J, Oze I, Pai RK, Pan ZZ, Pharoah PDP, Playdon MC, Ren ZF, Schoen RE, Shin A, Shin MH, Shu XO, Sun X, Tangen CM, Tanikawa C, Ulrich CM, van Duijnhoven FJB, Van Guelpen B, Wolk A, Woods MO, Wu AH, Peters U, Zheng W. Large-scale Integrated Analysis of Genetics and Metabolomic Data Reveals Potential Links Between Lipids and Colorectal Cancer Risk. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022 Jun 1;31(6):1216-1226. PMID: 35266989
  • Li X, Hoogland AI, Small BJ, Crowder SL, Gonzalez BD, Oswald LB, Sleight AG, Nguyen N, Lorona NC, Damerell V, Komrokji KR, Mooney K, Playdon MC, Ulrich CM, Li CI, Shibata D, Toriola AT, Ose J, Peoples AR, Siegel EM, Bower JE, Schneider M, Gigic B, Figueiredo JC, Jim HSL. Trajectories and risk factors of fatigue following colorectal cancer diagnosis. Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. 2023 Oct;25(10):2054-2063. Epub 2023 Sep 12. PMID: 37700526
  • Schmidt DR, Gramatikov IMT, Sheen A, Williams CL, Hurwitz M, Dodge LE, Holupka E, Kiger WS 3rd, Cornwall-Brady MR, Huang W, Mak HH, Cormier KS, Condon C, Dane Wittrup K, Yilmaz ÖH, Stevenson MA, Down JD, Floyd SR, Roper J, Vander Heiden MG. Ablative radiotherapy improves survival but does not cure autochthonous mouse models of prostate and colorectal cancer. Communications medicine. 2023 Aug 9;3(1):108. PMID: 37558833
  • Crowder SL, Li X, Himbert C, Viskochil R, Hoogland AI, Gudenkauf LM, Oswald LB, Gonzalez BD, Small BJ, Ulrich CM, Ose J, Peoples AR, Li CI, Shibata D, Toriola AT, Gigic B, Playdon MC, Hardikar S, Bower J, Siegel EM, Figueiredo JC, Jim HSL. Relationships Among Physical Activity, Sleep, and Cancer-related Fatigue: Results From the International ColoCare Study. Annals of behavioral medicine : a publication of the Society of Behavioral Medicine. 2024 Feb 10;58(3):156-166. PMID: 38141201
  • Ose J, Gigic B, Hardikar S, Lin T, Himbert C, Warby CA, Peoples AR, Lindley CL, Boehm J, Schrotz-King P, Figueiredo JC, Toriola AT, Siegel EM, Li CI, Ulrich A, Schneider M, Shibata D, Ulrich CM. Presurgery Adhesion Molecules and Angiogenesis Biomarkers Are Differently Associated with Outcomes in Colon and Rectal Cancer: Results from the ColoCare Study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022 Aug 2;31(8):1650-1660. PMID: 35667092
  • Sedlak JC, Yilmaz ÖH, Roper J. Metabolism and Colorectal Cancer. Annual review of pathology. 2023 Jan 24;18:467-492. Epub 2022 Nov 2. PMID: 36323004
  • Himbert C, Warby CA, Gigic B, Ose J, Lin T, Viskochil R, Peoples AR, Ashworth A, Schrotz-King P, Scaife CL, Cohan JN, Jedrzkiewicz J, Schirmacher P, Grady WM, Cohen SA, Krane M, Figueiredo JC, Toriola AT, Siegel EM, Shibata D, Round JL, Huang LC, Li CI, Schneider M, Ulrich A, Hardikar S, Ulrich CM. Associations of Individual and Combined Physical Activity and Body Mass Index Groups with Proinflammatory Biomarkers among Colorectal Cancer Patients. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022 Dec 5;31(12):2148-2156. PMID: 36099423