Principal Investigator

Awardee Organization

University Of Tx Md Anderson Can Ctr
United States

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

Uncovering the Role of Colorectal Stem Cells on Disease Penetrance in Lynch Syndrome

Lynch syndrome is an autosomal dominant hereditary condition predisposing patients to develop mainly colorectal cancer with an estimated life-time risk as high as 80%, which is secondary to germline alterations in the DNA mismatch repair genes. However, it has an incomplete disease penetrance that varies widely depending on the genotype, age and gender of the patients. Penetrance studies looking into epidemiological factors as well as single gene-to-gene interactions within the metabolism of xenobiotics have failed to refine risk estimations in Lynch Syndrome, thus leading to boiler plate recommendations for colorectal cancer screening. Exposure to non-steroidal anti-inflammatory agents, in particular Aspirin, has been the only factor that has been able to modify disease penetrance (60% risk reduction). Our long-term goal is to explain the differences observed in colorectal penetrance in this patient population by understanding the molecular events driving colorectal carcinogenesis in Lynch Syndrome, so we can implement precision screening and chemoprevention. The objective of this application is to characterize the cellular and molecular changes induced by chemoprevention with non-steroidal antiinflammatory agents and Statins on colorectal stem cells that lead to reduction of colorectal cancer penetrance. Our central hypothesis is that variation of colorectal cancer penetrance among Lynch Syndrome patients is secondary to molecular changes directly involving the colorectal stem cell niche of the normal at-risk mucosa. The rationale supporting this proposal is based on our observations that (1) at-risk mucosa and polyps from Lynch Syndrome patients show transcriptional differences in intestinal stem cell signatures compared to normal mucosa of healthy controls; (2) chemoprevention with Simvastatin induces a profound modulation of colorectal cancer penetrance in an intestinal-specific mouse model of Lynch Syndrome; (3) chemoprevention with Simvastatin and Naproxen decreases intestinal stem cell markers and simultaneously increases differentiation markers in at-risk mucosa of Lynch Syndrome animal models. We propose to pursue the following three specific aims: (1) to define a signature of mismatch repair-deficient intestinal stem cells in vivo; (2) to assess the modulatory effect of Simvastatin and Naproxen as chemopreventive interventions on mismatch repair-deficient colorectal stem cells using patient-derived organoids and 3) to assess changes in stem cell and epithelial differentiation markers in normal colorectal mucosa biopsies of LS patients exposed to Naproxen in a Phase I chemoprevention trial. The innovation of this study lies in the use of chemopreventive agents as modifying tools of cancer penetrance to assess the role of colorectal stem cells and their related molecular pathways in the variation of colorectal cancer penetrance in Lynch Syndrome. This contribution will be significant because it will lead to the discovery of molecular markers for cancer risk prediction that will allow designing personalized plans for screening and preventive interventions in Lynch Syndrome patients.


  • Valle L, Vilar E, Tavtigian SV, Stoffel EM. Genetic predisposition to colorectal cancer: syndromes, genes, classification of genetic variants and implications for precision medicine. The Journal of pathology. 2019 Apr;247(5):574-588. Epub 2019 Feb 20. PMID: 30584801
  • Gebert J, Gelincik O, Oezcan-Wahlbrink M, Marshall JD, Hernandez-Sanchez A, Urban K, Long M, Cortes E, Tosti E, Katzenmaier EM, Song Y, Elsaadi A, Deng N, Vilar E, Fuchs V, Nelius N, Yuan YP, Ahadova A, Sei S, Shoemaker RH, Umar A, Wei L, Liu S, Bork P, Edelmann W, von Knebel Doeberitz M, Lipkin SM, Kloor M. Recurrent Frameshift Neoantigen Vaccine Elicits Protective Immunity With Reduced Tumor Burden and Improved Overall Survival in a Lynch Syndrome Mouse Model. Gastroenterology. 2021 Oct;161(4):1288-1302.e13. Epub 2021 Jul 2. PMID: 34224739
  • Noah TK, Lo YH, Price A, Chen G, King E, Washington MK, Aronow BJ, Shroyer NF. SPDEF functions as a colorectal tumor suppressor by inhibiting β-catenin activity. Gastroenterology. 2013 May;144(5):1012-1023.e6. Epub 2013 Feb 1. PMID: 23376423
  • Lo YH, Noah TK, Chen MS, Zou W, Borras E, Vilar E, Shroyer NF. SPDEF Induces Quiescence of Colorectal Cancer Cells by Changing the Transcriptional Targets of β-catenin. Gastroenterology. 2017 Jul;153(1):205-218.e8. Epub 2017 Apr 5. PMID: 28390865
  • Chang K, Taggart MW, Reyes-Uribe L, Borras E, Riquelme E, Barnett RM, Leoni G, San Lucas FA, Catanese MT, Mori F, Diodoro MG, You YN, Hawk ET, Roszik J, Scheet P, Kopetz S, Nicosia A, Scarselli E, Lynch PM, McAllister F, Vilar E. Immune Profiling of Premalignant Lesions in Patients With Lynch Syndrome. JAMA oncology. 2018 Aug 1;4(8):1085-1092. PMID: 29710228
  • Chang K, McAllister F, Vilar E. Transcriptomic-Assisted Immune and Neoantigen Profiling in Premalignancy. Methods in molecular biology (Clifton, N.J.). 2022;2435:95-105. PMID: 34993941
  • Willis JA, Overman MJ, Vilar E. Mismatch Repair-Proficient Colorectal Cancer: Finding the Right TiME to Respond. Clinical cancer research : an official journal of the American Association for Cancer Research. 2019 Sep 1;25(17):5185-5187. Epub 2019 Jul 1. PMID: 31263028
  • Willis JA, Reyes-Uribe L, Chang K, Lipkin SM, Vilar E. Immune Activation in Mismatch Repair-Deficient Carcinogenesis: More Than Just Mutational Rate. Clinical cancer research : an official journal of the American Association for Cancer Research. 2020 Jan 1;26(1):11-17. Epub 2019 Aug 5. PMID: 31383734
  • Reyes-Uribe L, Wu W, Gelincik O, Bommi PV, Francisco-Cruz A, Solis LM, Lynch PM, Lim R, Stoffel EM, Kanth P, Samadder NJ, Mork ME, Taggart MW, Milne GL, Marnett LJ, Vornik L, Liu DD, Revuelta M, Chang K, You YN, Kopelovich L, Wistuba II, Lee JJ, Sei S, Shoemaker RH, Szabo E, Richmond E, Umar A, Perloff M, Brown PH, Lipkin SM, Vilar E. Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa. Gut. 2021 Mar;70(3):555-566. Epub 2020 Jul 8. PMID: 32641470
  • Bommi PV, Bowen CM, Reyes-Uribe L, Wu W, Katayama H, Rocha P, Parra ER, Francisco-Cruz A, Ozcan Z, Tosti E, Willis JA, Wu H, Taggart MW, Burks JK, Lynch PM, Edelmann W, Scheet PA, Wistuba II, Sinha KM, Hanash SM, Vilar E. The Transcriptomic Landscape of Mismatch Repair-Deficient Intestinal Stem Cells. Cancer research. 2021 May 15;81(10):2760-2773. Epub 2021 Mar 18. PMID: 34003775
  • Bowen CM, Deng N, Reyes-Uribe L, Parra ER, Rocha P, Solis LM, Wistuba II, Sepeda VO, Vornik L, Perloff M, Szabo E, Umar A, Sinha KM, Brown PH, Vilar E. Naproxen chemoprevention induces proliferation of cytotoxic lymphocytes in Lynch Syndrome colorectal mucosa. Frontiers in immunology. 2023 May 3;14:1162669. doi: 10.3389/fimmu.2023.1162669. eCollection 2023. PMID: 37207208