Degree of Tissue Differentiation Dictates Susceptibility to BRAF-Driven Colorectal Cancer

被引：58

作者：

Tong, Kevin ^{[1
,2
]}

Pellon-Cardenas, Oscar ^{[1
,2
]}

Sirihorachai, Veerin R. ^{[1
,5
]}

Warder, Bailey N. ^{[1
]}

Kothari, Om A. ^{[1
]}

Perekatt, Ansu O. ^{[1
,2
]}

Fokas, Emily E. ^{[1
]}

Fullem, Robert L. ^{[1
,6
]}

Zhou, Anbo ^{[1
]}

Thackray, Joshua K. ^{[1
]}

Tran, Hiep ^{[3
]}

Zhang, Lanjing ^{[2
,4
]}

Xing, Jinchuan ^{[1
]}

Verzi, Michael P. ^{[1
,2
]}

机构：

[1] Rutgers State Univ, HGINJ, Dept Genet, 145 Bevier Rd, Piscataway Township, NJ 08854 USA

[2] Rutgers Canc Inst New Jersey CINJ, 195 Little Albany St, New Brunswick, NJ 08903 USA

[3] Rutgers State Univ, Waksman Inst, Piscataway, NJ 08854 USA

[4] Univ Med Ctr Princeton, Dept Pathol, Plainsboro, NJ 08536 USA

[5] Univ Michigan, Dept Canc Biol, 109 Zina Pitcher Pl, Ann Arbor, MI 48109 USA

[6] NHGRI, 5635 Fishers Lane, Rockville, MD 20892 USA

来源：

CELL REPORTS | 2017年 / 21卷 / 13期

关键词：

INTESTINAL STEM-CELLS; POOR-PROGNOSIS; COLON-CANCER; CDX2; EXPRESSION; CRYPT; PROGRESSION; SENESCENCE; MODEL; METAPLASIA;

D O I：

10.1016/j.celrep.2017.11.104

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Oncogenic mutations in BRAF are believed to initiate serrated colorectal cancers; however, the mechanisms of BRAF-driven colon cancer are unclear. We find that oncogenic BRAF paradoxically suppresses stem cell renewal and instead promotes differentiation. Correspondingly, tumor formation is inefficient in BRAF-driven mouse models of colon cancer. By reducing levels of differentiation via genetic manipulation of either of two distinct differentiation-promoting factors (Smad4 or Cdx2), stem cell activity is restored in BRAF(V600E) intestines, and the oncogenic capacity of BRAF(V600E) is amplified. In human patients, we observe that reduced levels of differentiation in normal tissue is associated with increased susceptibility to serrated colon tumors. Together, these findings help resolve the conditions necessary for BRAF-driven colon cancer initiation. Additionally, our results predict that genetic and/or environmental factors that reduce tissue differentiation will increase susceptibility to serrated colon cancer. These findings offer an opportunity to identify susceptible individuals by assessing their tissue-differentiation status.

引用

页码：3833 / 3845

页数：13

共 51 条

[1] Loss of CDX2 expression is associated with poor prognosis in colorectal cancer patients [J].

Bae, Jeong Mo ;

Lee, Tae Hun ;

Cho, Nam-Yun ;

Kim, Tae-You ;

Kang, Gyeong Hoon .

WORLD JOURNAL OF GASTROENTEROLOGY, 2015, 21 (05) :1457-1467

[2] Identification of stem cells in small intestine and colon by marker gene Lgr5 [J].

Barker, Nick ;

van Es, Johan H. ;

Kuipers, Jeroen ;

Kujala, Pekka ;

van den Born, Maaike ;

Cozijnsen, Miranda ;

Haegebarth, Andrea ;

Korving, Jeroen ;

Begthel, Harry ;

Peters, Peter J. ;

Clevers, Hans .

NATURE, 2007, 449 (7165) :1003-U1

[3] Crypt stem cells as the cells-of-origin of intestinal cancer [J].

Barker, Nick ;

Ridgway, Rachel A. ;

van Es, Johan H. ;

van de Wetering, Marc ;

Begthel, Harry ;

van den Born, Maaike ;

Danenberg, Esther ;

Clarke, Alan R. ;

Sansom, Owen J. ;

Clevers, Hans .

NATURE, 2009, 457 (7229) :608-U119

[4] V600EBraf induces gastrointestinal crypt senescence and promotes tumour progression through enhanced CpG methylation of p16INK4a [J].

Carragher, Linda A. S. ;

Snell, Kimberley R. ;

Giblett, Susan M. ;

Aldridge, Victoria S. S. ;

Patel, Bipin ;

Cook, Simon J. ;

Winton, Doug J. ;

Marais, Richard ;

Pritchard, Catrin A. .

EMBO MOLECULAR MEDICINE, 2010, 2 (11) :458-471

[5] E2f1-3 switch from activators in progenitor cells to repressors in differentiating cells [J].

Chong, Jean-Leon ;

Wenzel, Pamela L. ;

Saenz-Robles, M. Teresa ;

Nair, Vivek ;

Ferrey, Antoney ;

Hagan, John P. ;

Gomez, Yorman M. ;

Sharma, Nidhi ;

Chen, Hui-Zi ;

Ouseph, Madhu ;

Wang, Shu-Huei ;

Trikha, Prashant ;

Culp, Brian ;

Mezache, Louise ;

Winton, Douglas J. ;

Sansom, Owen J. ;

Chen, Danian ;

Bremner, Rod ;

Cantalupo, Paul G. ;

Robinson, Michael L. ;

Pipas, James M. ;

Leone, Gustavo .

NATURE, 2009, 462 (7275) :930-934

[6] The Intestinal Crypt, A Prototype Stem Cell Compartment [J].

Clevers, Hans .

CELL, 2013, 154 (02) :274-284

[7] Wnt/β-Catenin Signaling and Disease [J].

Clevers, Hans ;

Nusse, Roel .

CELL, 2012, 149 (06) :1192-1205

[8] CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer [J].

Dalerba, Piero ;

Sahoo, Debashis ;

Paik, Soonmyung ;

Guo, Xiangqian ;

Yothers, Greg ;

Song, Nan ;

Wilcox-Fogel, Nate ;

Forgo, Erna ;

Rajendran, Pradeep S. ;

Miranda, Stephen P. ;

Hisamori, Shigeo ;

Hutchison, Jacqueline ;

Kalisky, Tomer ;

Qian, Dalong ;

Wolmark, Norman ;

Fisher, George A. ;

van de Rijn, Matt ;

Clarke, Michael F. .

NEW ENGLAND JOURNAL OF MEDICINE, 2016, 374 (03) :211-222

[9] A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors [J].

Dankort, David ;

Filenova, Elena ;

Collado, Manuel ;

Serrano, Manuel ;

Jones, Kirk ;

McMahon, Martin .

GENES & DEVELOPMENT, 2007, 21 (04) :379-384

[10] Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions [J].

De Sousa E Melo, Felipe ;

Wang, Xin ;

Jansen, Marnix ;

Fessler, Evelyn ;

Trinh, Anne ;

de Rooij, Laura P. M. H. ;

de Jong, Joan H. ;

de Boer, Onno J. ;

van Leersum, Ronald ;

Bijlsma, Maarten F. ;

Rodermond, Hans ;

van der Heijden, Maartje ;

van Noesel, Carel J. M. ;

Tuynman, Jurriaan B. ;

Dekker, Evelien ;

Markowetz, Florian ;

Medema, Jan Paul ;

Vermeulen, Louis .

NATURE MEDICINE, 2013, 19 (05) :614-618

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