A Genetic Progression Model of Braf(V600E)-induced Intestinal Tumorigenesis Reveals Targets for Therapeutic Intervention

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2013 Jul 13

PMID 23845441

Citations 125

Authors

Roland Rad

Juan Cadinanos

Lena Rad

Ignacio Varela

Alexander Strong

Lydia Kriegl

Fernando Constantino-Casas

Stefan Eser

Maren Hieber

Barbara Seidler

Stacey Price

Mario F Fraga

Vincenzo Calvanese

Gary Hoffman

Hannes Ponstingl

Gunter Schneider

Kosuke Yusa

Carolyn Grove

Roland M Schmid

Wei Wang

George Vassiliou

Thomas Kirchner

Ultan McDermott

Pentao Liu

Dieter Saur

Allan Bradley

Affiliations

Soon will be listed here.

Abstract

We show that BRAF(V600E) initiates an alternative pathway to colorectal cancer (CRC), which progresses through a hyperplasia/adenoma/carcinoma sequence. This pathway underlies significant subsets of CRCs with distinctive pathomorphologic/genetic/epidemiologic/clinical characteristics. Genetic and functional analyses in mice revealed a series of stage-specific molecular alterations driving different phases of tumor evolution and uncovered mechanisms underlying this stage specificity. We further demonstrate dose-dependent effects of oncogenic signaling, with physiologic Braf(V600E) expression being sufficient for hyperplasia induction, but later stage intensified Mapk-signaling driving both tumor progression and activation of intrinsic tumor suppression. Such phenomena explain, for example, the inability of p53 to restrain tumor initiation as well as its importance in invasiveness control, and the late stage specificity of its somatic mutation. Finally, systematic drug screening revealed sensitivity of this CRC subtype to targeted therapeutics, including Mek or combinatorial PI3K/Braf inhibition.

Citing Articles

Model systems to study tumor-microbiome interactions in early-onset colorectal cancer.

Richter K, Wrage M, Krekeler C, De Oliveira T, Conradi L, Menck K EMBO Mol Med. 2025; 17(3):395-413.

PMID: 39948421 PMC: 11903813. DOI: 10.1038/s44321-025-00198-3.

Analysis of Immunohistochemical Expression of BRAF (V600E) Mutation in Serrated Colorectal Polyps: A Study from Tertiary Hospital in Oman.

Al Ghafri A, Sayed S, Al Badi S, Al Rashdi A, Al Husaini S, Qureshi A Asian Pac J Cancer Prev. 2024; 25(7):2567-2571.

PMID: 39068592 PMC: 11480628. DOI: 10.31557/APJCP.2024.25.7.2567.

FAK loss reduces BRAF-induced ERK phosphorylation to promote intestinal stemness and cecal tumor formation.

Gao C, Ge H, Kuan S, Cai C, Lu X, Esni F Elife. 2024; 13.

PMID: 38921956 PMC: 11208045. DOI: 10.7554/eLife.94605.

Epithelial aPKC deficiency leads to stem cell loss preceding metaplasia in colorectal cancer initiation.

Kinoshita H, Martinez-Ordonez A, Cid-Diaz T, Han Q, Duran A, Muta Y Dev Cell. 2024; 59(15):1972-1987.e8.

PMID: 38815584 PMC: 11303105. DOI: 10.1016/j.devcel.2024.05.001.

Bacillamide D produced by Bacillus cereus from the mouse intestinal bacterial collection (miBC) is a potent cytotoxin in vitro.

Hohmann M, Brunner V, Johannes W, Schum D, Carroll L, Liu T Commun Biol. 2024; 7(1):655.

PMID: 38806706 PMC: 11133360. DOI: 10.1038/s42003-024-06208-3.

References

Flaherty K, Robert C, Hersey P, Nathan P, Garbe C, Milhem M . Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012; 367(2):107-14. DOI: 10.1056/NEJMoa1203421. View

Sherr C, McCormick F . The RB and p53 pathways in cancer. Cancer Cell. 2002; 2(2):103-12. DOI: 10.1016/s1535-6108(02)00102-2. View

Rex D, Ahnen D, Baron J, Batts K, Burke C, Burt R . Serrated lesions of the colorectum: review and recommendations from an expert panel. Am J Gastroenterol. 2012; 107(9):1315-29. PMC: 3629844. DOI: 10.1038/ajg.2012.161. View

Feng Y, Bommer G, Zhao J, Green M, Sands E, Zhai Y . Mutant KRAS promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool. Gastroenterology. 2011; 141(3):1003-1013.e1-10. PMC: 3163826. DOI: 10.1053/j.gastro.2011.05.007. View

Bettington M, Walker N, Clouston A, Brown I, Leggett B, Whitehall V . The serrated pathway to colorectal carcinoma: current concepts and challenges. Histopathology. 2013; 62(3):367-86. DOI: 10.1111/his.12055. View

Palmero I, Pantoja C, Serrano M . p19ARF links the tumour suppressor p53 to Ras. Nature. 1998; 395(6698):125-6. DOI: 10.1038/25870. View

Garnett M, Edelman E, Heidorn S, Greenman C, Dastur A, Lau K . Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012; 483(7391):570-5. PMC: 3349233. DOI: 10.1038/nature11005. View

Flaherty K, Infante J, Daud A, Gonzalez R, Kefford R, Sosman J . Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012; 367(18):1694-703. PMC: 3549295. DOI: 10.1056/NEJMoa1210093. View

Lin A, Barradas M, Stone J, Van Aelst L, Serrano M, Lowe S . Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 1998; 12(19):3008-19. PMC: 317198. DOI: 10.1101/gad.12.19.3008. View

10.

Yachida S, Mudali S, Martin S, Montgomery E, Iacobuzio-Donahue C . Beta-catenin nuclear labeling is a common feature of sessile serrated adenomas and correlates with early neoplastic progression after BRAF activation. Am J Surg Pathol. 2009; 33(12):1823-32. PMC: 2788075. DOI: 10.1097/PAS.0b013e3181b6da19. View

11.

Kambara T, Simms L, Whitehall V, Spring K, Wynter C, Walsh M . BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut. 2004; 53(8):1137-44. PMC: 1774130. DOI: 10.1136/gut.2003.037671. View

12.

Feldser D, Kostova K, Winslow M, Taylor S, Cashman C, Whittaker C . Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature. 2010; 468(7323):572-5. PMC: 3003305. DOI: 10.1038/nature09535. View

13.

Torlakovic E, Skovlund E, Snover D, Torlakovic G, Nesland J . Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol. 2002; 27(1):65-81. DOI: 10.1097/00000478-200301000-00008. View

14.

Yang S, Farraye F, Mack C, Posnik O, OBrien M . BRAF and KRAS Mutations in hyperplastic polyps and serrated adenomas of the colorectum: relationship to histology and CpG island methylation status. Am J Surg Pathol. 2004; 28(11):1452-9. DOI: 10.1097/01.pas.0000141404.56839.6a. View

15.

Chan T, Zhao W, Leung S, Yuen S . BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res. 2003; 63(16):4878-81. View

16.

Junttila M, Karnezis A, Garcia D, Madriles F, Kortlever R, Rostker F . Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature. 2010; 468(7323):567-71. PMC: 3011233. DOI: 10.1038/nature09526. View

17.

Michaloglou C, Vredeveld L, Soengas M, Denoyelle C, Kuilman T, van der Horst C . BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005; 436(7051):720-4. DOI: 10.1038/nature03890. View

18.

Bennecke M, Kriegl L, Bajbouj M, Retzlaff K, Robine S, Jung A . Ink4a/Arf and oncogene-induced senescence prevent tumor progression during alternative colorectal tumorigenesis. Cancer Cell. 2010; 18(2):135-46. DOI: 10.1016/j.ccr.2010.06.013. View

19.

Murphy D, Junttila M, Pouyet L, Karnezis A, Shchors K, Bui D . Distinct thresholds govern Myc's biological output in vivo. Cancer Cell. 2008; 14(6):447-57. PMC: 2723751. DOI: 10.1016/j.ccr.2008.10.018. View

20.

Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D . Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012; 483(7387):100-3. DOI: 10.1038/nature10868. View