Role of Oncogenic K-Ras in Cancer Stem Cell Activation by Aberrant Wnt/β-Catenin Signaling

Moon, Byoung San; Jeong, Woo Jeong; Park, Jieun; Kim, Taeil; Min, Do Sik; Choi, Kang Yell

doi:10.1093/jnci/djt373

Cited by 156 publications

(167 citation statements)

References 31 publications

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“…Cre-mediated mutations of Apc and Kras in intestinal stem cells as well as xenograft studies with human cancer cells bearing APC and KRAS mutations transplanted into mice have shown that oncogenic KRAS enhances tumor progression in CRC harboring APC mutations (20,33). Intriguingly, simultaneous Apc deletion and oncogenic Kras hyperactivation transformed differentiated Car1-expressing cells into tumor-initiating cells with cancer-stem-cell characteristics, arguing that cancer can also be generated in a top-down model, where differentiated cells acquire multiple mutations.…”

Section: Discussionmentioning

confidence: 99%

Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research

Tetteh

Kretzschmar

Begthel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Current mouse models for colorectal cancer often differ significantly from human colon cancer, being largely restricted to the small intestine. Here, we aim to develop a colon-specific inducible mouse model that can faithfully recapitulate human colon cancer initiation and progression. Carbonic anhydrase I (Car1) is a gene expressed uniquely in colonic epithelial cells. We generated a colon-specific inducible Car1 CreER knock-in (KI) mouse with broad Cre activity in epithelial cells of the proximal colon and cecum. Deletion of the tumor suppressor gene Apc using the Car1 CreER KI caused tumor formation in the cecum but did not yield adenomas in the proximal colon. Mutation of both Apc and Kras yielded microadenomas in both the cecum and the proximal colon, which progressed to macroadenomas with significant morbidity. Aggressive carcinomas with some invasion into lymph nodes developed upon combined induction of oncogenic mutations of Apc, Kras, p53, and Smad4. Importantly, no adenomas were observed in the small intestine. Additionally, we observed tumors from differentiated Car1-expressing cells with Apc/Kras mutations, suggesting that a top-down model of intestinal tumorigenesis can occur with multiple mutations. Our results establish the Car1 CreER KI as a valuable mouse model to study colon-specific tumorigenesis and metastasis as well as cancer-cell-of-origin questions.

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Section: Discussionmentioning

confidence: 99%

Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research

Tetteh

Kretzschmar

Begthel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Wnt and MAPK signaling have been shown to co-operate during conventional intestinal tumor progression, with APC/β-catenin pathway mutations occurring first: nuclear localization of β-catenin and expression of cancer stem cell markers after loss of APC are increased by mutational activation of the MAPK-controlling GTPase KRAS, 48,49 and in turn KRAS can be stabilized by β-catenin activity. 50 In contrast, activation of MAPK signaling downstream of oncogenic BRAF can inhibit β-catenin effects in melanoma.…”

Section: Discussionmentioning

confidence: 99%

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

et al. 2014

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Colon cancer cells frequently carry mutations that activate the β-catenin and mitogen-activated protein kinase (MAPK) signaling cascades. Yet how oncogenic alterations interact to control cellular hierarchies during tumor initiation and progression is largely unknown. We found that oncogenic BRAF modulates gene expression associated with cell differentiation in colon cancer cells. We therefore engineered a mouse with an inducible oncogenic BRAF transgene, and analyzed BRAF effects on cellular hierarchies in the intestinal epithelium in vivo and in primary organotypic culture. We demonstrate that transgenic expression of oncogenic BRAF in the mouse strongly activated MAPK signal transduction, resulted in the rapid development of generalized serrated dysplasia, but unexpectedly also induced depletion of the intestinal stem cell (ISC) pool. Histological and gene expression analyses indicate that ISCs collectively converted to short-lived progenitor cells after BRAF activation. As Wnt/β-catenin signals encourage ISC identity, we asked whether β-catenin activity could counteract oncogenic BRAF. Indeed, we found that intestinal organoids could be partially protected from deleterious oncogenic BRAF effects by Wnt3a or by small-molecule inhibition of GSK3β. Similarly, transgenic expression of stabilized β-catenin in addition to oncogenic BRAF partially prevented loss of stem cells in the mouse intestine. We also used BRAF V637E knock-in mice to follow changes in the stem cell pool during serrated tumor progression and found ISC marker expression reduced in serrated hyperplasia forming after BRAF activation, but intensified in progressive dysplastic foci characterized by additional mutations that activate the Wnt/β-catenin pathway. Our study suggests that oncogenic alterations activating the MAPK and Wnt/β-catenin pathways must be consecutively and coordinately selected to assure stem cell maintenance during colon cancer initiation and progression. Notably, loss of stem cell identity upon induction of BRAF/MAPK activity may represent a novel fail-safe mechanism protecting intestinal tissue from oncogene activation.

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“…Because of its importance in cancer, the Ras-ERK MAPK signaling pathway has been an attractive target for anti-cancer therapy. For example, Moon et al examined the role of two genes, APC and K-Ras, working in tandem in initiating colorectal cancer progression (Moon et al, 2014). The group's data showed that a gain-offunction mutation of the oncogenic K-Ras, fixing it in the active, GTP-bound conformation, accelerates the ERK pathway, which in turn activates the Wnt/β-catenin pathway, inducing cancer stem cell marker expression in colorectal cancer cells (Moon et al, 2014).…”

Section: Ras Signaling and Cancer Stem Cellsmentioning

confidence: 99%

“…For example, Moon et al examined the role of two genes, APC and K-Ras, working in tandem in initiating colorectal cancer progression (Moon et al, 2014). The group's data showed that a gain-offunction mutation of the oncogenic K-Ras, fixing it in the active, GTP-bound conformation, accelerates the ERK pathway, which in turn activates the Wnt/β-catenin pathway, inducing cancer stem cell marker expression in colorectal cancer cells (Moon et al, 2014). Increased contribution to tumorigenesis and liver metastasis in K-Ras (gf) was observed in the presence of loss-of-function mutations in adenomatous polyposis coli (APC), a negative regulator of β-catenin concentration, another condition characteristic of initial and intermediate stage colorectal cancer (Moon et al, 2014).…”

Section: Ras Signaling and Cancer Stem Cellsmentioning

confidence: 99%

“…The group's data showed that a gain-offunction mutation of the oncogenic K-Ras, fixing it in the active, GTP-bound conformation, accelerates the ERK pathway, which in turn activates the Wnt/β-catenin pathway, inducing cancer stem cell marker expression in colorectal cancer cells (Moon et al, 2014). Increased contribution to tumorigenesis and liver metastasis in K-Ras (gf) was observed in the presence of loss-of-function mutations in adenomatous polyposis coli (APC), a negative regulator of β-catenin concentration, another condition characteristic of initial and intermediate stage colorectal cancer (Moon et al, 2014). The study utilized specimens from human colorectal cancer patients and APC Min/+ /K-Ras LA2 mice, which were studied for their ability to form spheroids in vitro and tumors in vivo, respectively.…”

Section: Ras Signaling and Cancer Stem Cellsmentioning

confidence: 99%

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Caenorhabditis elegans: A Model System for Anti-Cancer Drug Discovery and Therapeutic Target Identification

Kobet¹,

Pan²,

Zhang³

et al. 2014

Biomol Ther

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Role of Oncogenic K-Ras in Cancer Stem Cell Activation by Aberrant Wnt/β-Catenin Signaling

Abstract: K-Ras mutation activates CSCs, contributing to colorectal tumorigenesis and metastasis in CRC cells harboring APC mutations. Initial activation of β-catenin by APC loss and further enhancement through K-Ras mutation induces CD44, CD133, and CD166 expression.

Cited by 156 publications

References 31 publications

Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research

Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

Caenorhabditis elegans: A Model System for Anti-Cancer Drug Discovery and Therapeutic Target Identification

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