Wnt signaling suppresses MAPK-driven proliferation of intestinal stem cells

Kabiri, Zahra; Greicius, Gediminas; Zaribafzadeh, Hamed; Hemmerich, Amanda; Counter, Christopher M.; Virshup, David M.

doi:10.1172/jci99325

Cited by 78 publications

(82 citation statements)

References 28 publications

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“…A recent study suggested that WNT signaling suppression induces conversion of ISCs into TA cells, resulting in accelerated proliferation. 40 Based on transcriptome profile of Klf5-null ISCs that showed reduction of WNT target genes, we speculate that Klf5-null ISCs undergo premature differentiation to rapidly-cycling enterocyte precursors via suppression of WNT signaling pathway. However it remains possible that Klf5-null ISCs spontaneously lose Lgr5 expression, thus further contributing to loss of ISCs.…”

Section: Discussionmentioning

confidence: 82%

Krüppel-like Factor 5 Regulates Stemness, Lineage Specification, and Regeneration of Intestinal Epithelial Stem Cells

Kim

Saxena

Maharjan

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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Lgr5 þ ISCs lacking KLF5 proliferate faster than control ISCs but fail to self-renew, resulting in a depleted ISC compartment. Transcriptome analysis revealed that Klf5-null Lgr5 þ cells lose ISC identity and prematurely differentiate. Following irradiation injury, which depletes Lgr5 þ ISCs, reserve Klf5-null progenitor cells fail to dedifferentiate and regenerate the epithelium. Absence of KLF5 inactivates numerous selected enhancer elements and direct transcriptional targets including canonical WNT-and NOTCHresponsive genes. Analysis of human intestinal tissues showed increased levels of KLF5 in the regenerating epithelium as compared to those of healthy controls. CONCLUSION: We conclude that ISC self-renewal, lineage specification, and precursor dedifferentiation require KLF5, by its ability to regulate epigenetic and transcriptional activities of ISC-specific gene sets. These findings have the potential for modulating ISC functions by targeting KLF5 in the intestinal epithelium.

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Section: Discussionmentioning

confidence: 82%

Krüppel-like Factor 5 Regulates Stemness, Lineage Specification, and Regeneration of Intestinal Epithelial Stem Cells

Kim

Saxena

Maharjan

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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“…Crosstalk between these pathways has been observed in other cellular contexts. In the mammalian intestine, reciprocal gradients of WNT and phosphorylated ERK1/2 control the balance between proliferation and differentiation of intestinal stem cells (Kabiri et al 2018). In one study, reduction of MEK activity via gut-specific ablation of Ptpn11 impacted the relative levels of TCF4 isoforms, which have differing b-catenin-dependent transactivation capacities (Heuberger et al 2014).…”

Section: Discussionmentioning

confidence: 99%

An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma

Zewdu

Mehrabad

Ingram

et al. 2020

Preprint

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Cancer cells often undergo lineage switching during their natural progression and in response to therapy. Lung adenocarcinomas (LUADs) exhibit a variety of differentiation states accompanied by dysregulation of lineage-specific transcription factors such as NKX2-1. Loss of NKX2-1 in human and murine LUAD leads to invasive mucinous adenocarcinoma (IMA), a subtype of lung cancer that exhibits pulmonary to gastric transdifferentiation. Human IMAs harbor a distinct spectrum of mutationally activated driver oncogenes compared to LUAD overall, suggesting that the transdifferentiation induced by NKX2-1 loss plays a context-dependent role in LUAD progression. Using genetically engineered mouse models, we find that NKX2-1 is required for optimal BRAF V600E driven lung tumor initiation but is dispensable for growth of established lung tumors. NKX2-1-deficient, BRAF V600E driven tumors morphologically resemble human IMA, have high levels of ERK phosphorylation and exhibit a distinct response to treatment with combined BRAF/MEK inhibitors. Whereas NKX2-1-positive tumor cells enter quiescence when treated with BRAF/MEK inhibitors, residual NKX2-1-negative cells fail to exit the cell cycle in response to the same therapy. Additionally, BRAF/MEK inhibitors induce canonical WNT signaling in NKX2-1negative lung tumor cells, which is accompanied by cell identity switching within the gastric lineage. Co-inhibition of MAPK and WNT pathways blocked elements of this lineage switch in vitro and interfered with cell cycle changes imposed by MAPK inhibition in vivo. Our data show that there is a complex and reciprocal relationship between lineage specifiers and oncogenic signaling pathways in the regulation of LUAD identity and suggest that lineage switching induced by targeted therapies may confer new therapeutic vulnerabilities.

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“…This would imply that high BRAF activity in BRAF-V600E cells would require low Wnt signaling, consistent with low levels of Axin2 and other Wnt target genes as well as the lack of APC mutation in MSI-H colon cancer cells with BRAF-V600E mutation 36 . Interestingly, in intestinal stem cells, high Wnt signaling and MAPK activity were shown to be incompatible as the two pathways seem to inhibit each other 35,37,38 . Taken together, these findings suggest that MSI-H tumors with BRAF-V600E mutation had low Wnt signaling due to inhibition the hyperactive MAPK signaling.…”

Section: Discussionmentioning

confidence: 99%

The most common RNF43 mutant G659Vfs41 is fully functional in inhibiting Wnt signaling and unlikely to play a role in tumorigenesis

Park

et al. 2019

Preprint

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RNF43 is an E3 ligase that inhibits Wnt signaling by ubiquitinating Wnt receptors for degradation. It is mutated in various cancer types with the most recurrent mutation being the frameshift G659Vfs41 with frequencies of ~5-8% in colon, stomach and endometrial cancers. The mutation has always been assumed to be loss-of-function that would lead to increased Wnt signaling and tumorigenesis, yet no functional characterization has been reported. We analyzed the distribution of the G659Vfs41 mutation and its association with other cancer gene mutations, and found that the mutation occurred nearly exclusively in tumors with low expression of the DNA mismatch repair gene MLH1. Mutant RNF43-G659Vfs41 was no different from wild type RNF43 in expression, localization, R-spondin binding, promotion of Wnt receptor degradation, inhibition of Wnt signaling. We also found that colon tumors with RNF43-G659Vfs41 had low expression of Wnt/β-catenin signaling markers and were frequently mutated in BRAF. A colon cancer cell line with RNF43-G659Vfs41 and BRAF-V600E mutations was uniquely sensitively to activation of Wnt/β-catenin signaling. These findings indicate that RNF43-G659Vfs41 is likely a passenger mutation in MLH1-down regulated tumors, not a loss-of-function driver mutation that facilitates tumorigenesis. Tumors with RNF43-G659Vfs41 and BRAF-V600E may be susceptible to activators of Wnt signaling.

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Wnt signaling suppresses MAPK-driven proliferation of intestinal stem cells

Cited by 78 publications

References 28 publications

Krüppel-like Factor 5 Regulates Stemness, Lineage Specification, and Regeneration of Intestinal Epithelial Stem Cells

Krüppel-like Factor 5 Regulates Stemness, Lineage Specification, and Regeneration of Intestinal Epithelial Stem Cells

An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma

The most common RNF43 mutant G659Vfs41 is fully functional in inhibiting Wnt signaling and unlikely to play a role in tumorigenesis

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