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Cited by 10Genetic factors in colorectal cancerDNA Repair MechanismsColorectal Cancer Treatments and Studies

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The Transcriptomic Landscape of Mismatch Repair-Deficient Intestinal Stem Cells

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Bommi, Prashant V., Bowen, Charles M., Reyes-Uribe, Laura, Wu, Wenhui, Katayama, Hiroyuki, Rocha, Pedro, Parra, Edwin R., Francisco-Cruz, Alejandro, Ozcan, Zuhal, Tosti, Elena, Willis, Jason A., Wu, Hong, Taggart, Melissa W., Burks, Jared K., Lynch, Patrick M., Edelmann, Winfried, Scheet, Paul A., Wistuba, Ignacio I., Sinha, Krishna M., Hanash, Samir M., Vilar, Eduardo·2021·Cancer Research
DOI 10.1158/0008-5472.can-20-2896PMC PMC8318201

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Abstract

Lynch syndrome is the most common cause of hereditary colorectal cancer and is secondary to germline alterations in one of four DNA mismatch repair (MMR) genes. Here we aimed to provide novel insights into the initiation of MMR-deficient (MMRd) colorectal carcinogenesis by characterizing the expression profile of MMRd intestinal stem cells (ISC). A tissue-specific MMRd mouse model (Villin-Cre;Msh2LoxP/LoxP) was crossed with a reporter mouse (Lgr5-EGFP-IRES-creERT2) to trace and isolate ISCs (Lgr5+) using flow cytometry. Three different ISC genotypes (Msh2-KO, Msh2-HET, and Msh2-WT) were isolated and processed for mRNA-seq and mass spectrometry, followed by bioinformatic analyses to identify expression signatures of complete MMRd and haplo-insufficiency. These findings were validated using qRT-PCR, IHC, and whole transcriptomic sequencing in mouse tissues, organoids, and a cohort of human samples, including normal colorectal mucosa, premalignant lesions, and early-stage colorectal cancers from patients with Lynch syndrome and patients with familial adenomatous polyposis (FAP) as controls. Msh2-KO ISCs clustered together with differentiated intestinal epithelial cells from all genotypes. Gene-set enrichment analysis indicated inhibition of replication, cell-cycle progression, and the Wnt pathway and activation of epithelial signaling and immune reaction. An expression signature derived from MMRd ISCs successfully distinguished MMRd neoplastic lesions of patients with Lynch syndrome from FAP controls. SPP1 was specifically upregulated in MMRd ISCs and colocalized with LGR5 in Lynch syndrome colorectal premalignant lesions and tumors. These results show that expression signatures of MMRd ISC recapitulate the initial steps of Lynch syndrome carcinogenesis and have the potential to unveil novel biomarkers of early cancer initiation. Significance: The transcriptomic and proteomic profile of MMR-deficient intestinal stem cells displays a unique set of genes with potential roles as biomarkers of cancer initiation and early progression.

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Research works printed but not linked: 43

  1. Lynch, 2015, Milestones of Lynch syndrome: 1895–2015, Nat Rev Cancer, 15, 181, 10.1038/nrc3878 · DOI
  2. Win, 2017, Prevalence and penetrance of major genes and polygenes for colorectal cancer, Cancer Epidemiol Biomarkers Prev, 26, 404, 10.1158/1055-9965.EPI-16-0693 · DOI
  3. Fearon, 2011, Molecular genetics of colorectal cancer, Annu Rev Pathol, 6, 479, 10.1146/annurev-pathol-011110-130235 · DOI · Paper page
  4. Bonadona, 2011, Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome, JAMA, 305, 2304, 10.1001/jama.2011.743 · DOI
  5. Stoffel, 2009, Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome, Gastroenterology, 137, 1621, 10.1053/j.gastro.2009.07.039 · DOI · Paper page
  6. Møller, 2017, Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database, Gut, 66, 464, 10.1136/gutjnl-2015-309675 · DOI
  7. Schmeler, 2006, Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome, N Engl J Med, 354, 261, 10.1056/NEJMoa052627 · DOI
  8. van Leerdam, 2019, Endoscopic management of Lynch syndrome and of familial risk of colorectal cancer: European Society of Gastrointestinal Endoscopy (ESGE) Guideline, Endoscopy, 51, 1082, 10.1055/a-1016-4977 · DOI
  9. Barker, 2014, Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration, Nat Rev Mol Cell Biol, 15, 19, 10.1038/nrm3721 · DOI
  10. Sato, 2013, Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications, Science, 340, 1190, 10.1126/science.1234852 · DOI · Paper page
  11. Vermeulen, 2014, Stem cell dynamics in homeostasis and cancer of the intestine, Nat Rev Cancer, 14, 468, 10.1038/nrc3744 · DOI
  12. Visvader, 2011, Cells of origin in cancer, Nature, 469, 314, 10.1038/nature09781 · DOI
  13. Barker, 2009, Crypt stem cells as the cells-of-origin of intestinal cancer, Nature, 457, 608, 10.1038/nature07602 · DOI
  14. Barker, 2007, Identification of stem cells in small intestine and colon by marker gene Lgr5, Nature, 449, 1003, 10.1038/nature06196 · DOI · Paper page
  15. Muñoz, 2012, The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent ‘+4’ cell markers, EMBO J, 31, 3079, 10.1038/emboj.2012.166 · DOI
  16. de Wind, 1995, Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer, Cell, 82, 321, 10.1016/0092-8674(95)90319-4 · DOI
  17. Vaish, 2007, Mismatch repair deficiencies transforming stem cells into cancer stem cells and therapeutic implications, Mol Cancer, 6, 26, 10.1186/1476-4598-6-26 · DOI
  18. Spira, 2017, Precancer Atlas to drive precision prevention trials, Cancer Res, 77, 1510, 10.1158/0008-5472.CAN-16-2346 · DOI
  19. Kucherlapati, 2010, An Msh2 conditional knockout mouse for studying intestinal cancer and testing anticancer agents, Gastroenterology, 138, 993, 10.1053/j.gastro.2009.11.009 · DOI
  20. Chang, 2018, Immune profiling of premalignant lesions in patients with Lynch syndrome, JAMA Oncol, 4, 1085, 10.1001/jamaoncol.2018.1482 · DOI
  21. Reyes-Uribe, 2021, Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa, Gut, 70, 555, 10.1136/gutjnl-2020-320946 · DOI
  22. Costales-Carrera, 2020, Comparative study of organoids from patient-derived normal and tumor colon and rectal tissue, Cancers, 12, 2302, 10.3390/cancers12082302 · DOI
  23. Tetteh, 2016, Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research, Proc Natl Acad Sci U S A, 113, 11859, 10.1073/pnas.1614057113 · DOI
  24. Kumar, 2018, Ca(2+)/nuclear factor of activated T cells signaling is enriched in early-onset rectal tumors devoid of canonical Wnt activation, J Mol Med, 96, 135, 10.1007/s00109-017-1607-4 · DOI
  25. Fischer, 2017, RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations, Sci Rep, 7, 15270, 10.1038/s41598-017-15704-y · DOI
  26. Storm, 2016, Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function, Nature, 529, 97, 10.1038/nature16466 · DOI
  27. Zhang, 2016, RPS7 inhibits colorectal cancer growth via decreasing HIF-1alpha-mediated glycolysis, Oncotarget, 7, 5800, 10.18632/oncotarget.6807 · DOI
  28. Zhou, 2013, Ribosomal protein S14 negatively regulates c-Myc activity, J Biol Chem, 288, 21793, 10.1074/jbc.M112.445122 · DOI
  29. Friedmann-Morvinski, 2014, Dedifferentiation and reprogramming: origins of cancer stem cells, EMBO Rep, 15, 244, 10.1002/embr.201338254 · DOI
  30. Cerretelli, 2020, Molecular pathology of Lynch syndrome, J Pathol, 250, 518, 10.1002/path.5422 · DOI
  31. Huang, 2009, Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis, Cancer Res, 69, 3382, 10.1158/0008-5472.CAN-08-4418 · DOI
  32. Kim, 2002, Osteopontin as a potential diagnostic biomarker for ovarian cancer, JAMA, 287, 1671, 10.1001/jama.287.13.1671 · DOI
  33. Rodrigues, 2007, The role of osteopontin in tumor progression and metastasis in breast cancer, Cancer Epidemiol Biomarkers Prev, 16, 1087, 10.1158/1055-9965.EPI-06-1008 · DOI
  34. Rangaswami, 2006, Osteopontin: role in cell signaling and cancer progression, Trends Cell Biol, 16, 79, 10.1016/j.tcb.2005.12.005 · DOI
  35. Cheng, 2019, Osteopontin promotes colorectal cancer cell invasion and the stem cell-like properties through the PI3K-AKT-GSK/3beta-beta/Catenin pathway, Med Sci Monit, 25, 3014, 10.12659/MSM.913185 · DOI
  36. Ng, 2015, Osteopontin overexpression induced tumor progression and chemoresistance to oxaliplatin through induction of stem-like properties in human colorectal cancer, Stem Cells Int, 2015, 247892, 10.1155/2015/247892 · DOI
  37. Zhu, 2019, Disruption of tumour-associated macrophage trafficking by the osteopontin-induced colony-stimulating factor-1 signalling sensitises hepatocellular carcinoma to anti-PD-L1 blockade, Gut, 68, 1653, 10.1136/gutjnl-2019-318419 · DOI · Paper page
  38. Chen, 2019, Symbiotic macrophage-glioma cell interactions reveal synthetic lethality in PTEN-null glioma, Cancer Cell, 35, 868, 10.1016/j.ccell.2019.05.003 · DOI
  39. Klement, 2018, An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion, J Clin Invest, 128, 5549, 10.1172/JCI123360 · DOI
  40. Shurin, 2018, Osteopontin controls immunosuppression in the tumor microenvironment, J Clin Invest, 128, 5209, 10.1172/JCI124918 · DOI
  41. Akcora, 2013, The CSF-1 receptor fashions the intestinal stem cell niche, Stem Cell Res, 10, 203, 10.1016/j.scr.2012.12.001 · DOI
  42. Wang, 2014, Tumor-derived GM-CSF promotes inflammatory colon carcinogenesis via stimulating epithelial release of VEGF, Cancer Res, 74, 716, 10.1158/0008-5472.CAN-13-1459 · DOI
  43. Lu, 2009, Systems-level dynamic analyses of fate change in murine embryonic stem cells, Nature, 462, 358, 10.1038/nature08575 · DOI

Metadata

Authors
Bommi, P. V., Bowen, C. M., Reyes-Uribe, L., Wu, W., Katayama, H., Rocha, P., Parra, E. R., Francisco-Cruz, A., Ozcan, Z., Tosti, E., Willis, J. A., Wu, H., Taggart, M. W., Burks, J. K., Lynch, P. M., Edelmann, W., Scheet, P. A., Wistuba, I. I., Sinha, K. M., Hanash, S. M., & Vilar, E.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • 2Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 3Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Albert Einstein College of Medicine (US)
Corresponding author
Vilar, Eduardo
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2021-03-18
Volume
81
Issue
10
Pages
2760-2773
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-20-2896
PMC
PMC8318201
OpenAlex
W3139451574
Cited by
10
References
3
Citations by year
2026: 1 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 2
FWCI
1.33
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIH (R01 CA219463)
  • Feinberg Family Foundation
  • Multi-Investigator Research Award (RP160668)
  • Cancer Prevention and Research Institute of Texas
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Keywords
Lynch syndrome, mismatch repair deficiency, intestinal stem cells, colorectal carcinogenesis, MSH2, haploinsufficiency, gene expression signatures, proteomic signatures, osteopontin, Lgr5, Wnt signaling, cell cycle inhibition, familial adenomatous polyposis, tumor markers, organoids
MeSH terms
Animals, Colorectal Neoplasms, Hereditary Nonpolyposis, Humans, Intestines, Mice, Inbred C57BL, Prognosis, Stem Cells, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Survival Rate, Apoptosis, Mice, Knockout, Proteome, Receptors, G-Protein-Coupled, Cell Proliferation, Mice, MutS Homolog 2 Protein, DNA Mismatch Repair, Transcriptome, Carcinogenesis

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