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Regenerative reprogramming of the intestinal stem cell state via Hippo signaling suppresses metastatic colorectal cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE152376 | GEO | 2020/06/24

REPOSITORIES: GEO

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Regenerative Reprogramming of the Intestinal Stem Cell State via Hippo Signaling Suppresses Metastatic Colorectal Cancer.

Project description:Although the Hippo transcriptional coactivator YAP is considered oncogenic in many tissues, its roles in intestinal homeostasis and colorectal cancer (CRC) remain controversial. Here, we demonstrate that the Hippo kinases LATS1/2 and MST1/2, which inhibit YAP activity, are required for maintaining Wnt signaling and canonical stem cell function. Hippo inhibition induces a distinct epithelial cell state marked by low Wnt signaling, a wound-healing response, and transcription factor Klf6 expression. Notably, loss of LATS1/2 or overexpression of YAP is sufficient to reprogram Lgr5+ cancer stem cells to this state and thereby suppress tumor growth in organoids, patient-derived xenografts, and mouse models of primary and metastatic CRC. Finally, we demonstrate that genetic deletion of YAP and its paralog TAZ promotes the growth of these tumors. Collectively, our results establish the role of YAP as a tumor suppressor in the adult colon and implicate Hippo kinases as therapeutic vulnerabilities in colorectal malignancies.

| S-EPMC10114498 | biostudies-literature

Regenerative reprogramming of the intestinal stem cell state via Hippo signaling suppresses metastatic colorectal cancer [DSS_scRNAseq]

2020-06-24 | GSE152369 | GEO

Regenerative reprogramming of the intestinal stem cell state via Hippo signaling suppresses metastatic colorectal cancer [Organoid_RNAseq]

2020-06-24 | GSE152374 | GEO

Regenerative reprogramming of the intestinal stem cell state via Hippo signaling suppresses metastatic colorectal cancer [LATS_scRNAseq]

2020-06-24 | GSE152370 | GEO

Regenerative reprogramming of the intestinal stem cell state via Hippo signaling suppresses metastatic colorectal cancer

Project description:Regenerative reprogramming of the intestinal stem cell state via Hippo signaling suppresses metastatic colorectal cancer

| PRJNA639123 | ENA

Regenerative reprogramming of the intestinal stem cell state via Hippo signaling suppresses metastatic colorectal cancer [LATS_scRNAseq]

Project description:Regenerative reprogramming of the intestinal stem cell state via Hippo signaling suppresses metastatic colorectal cancer [LATS_scRNAseq]

| PRJNA639120 | ENA

Regenerative reprogramming of the intestinal stem cell state via Hippo signaling suppresses metastatic colorectal cancer [Organoid_RNAseq]

Project description:Regenerative reprogramming of the intestinal stem cell state via Hippo signaling suppresses metastatic colorectal cancer [Organoid_RNAseq]

| PRJNA639128 | ENA

Regenerative reprogramming of the intestinal stem cell state via Hippo signaling suppresses metastatic colorectal cancer [DSS_scRNAseq]

Project description:Regenerative reprogramming of the intestinal stem cell state via Hippo signaling suppresses metastatic colorectal cancer [DSS_scRNAseq]

| PRJNA639119 | ENA

CSRP2 suppresses colorectal cancer progression <i>via</i> p130Cas/Rac1 axis-meditated ERK, PAK, and HIPPO signaling pathways.

Project description:Metastasis is a major cause of death in patients with colorectal cancer (CRC). Cysteine-rich protein 2 (CSRP2) has been recently implicated in the progression and metastasis of a variety of cancers. However, the biological functions and underlying mechanisms of CSRP2 in the regulation of CRC progression are largely unknown. Methods: Immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR) and Western blotting (WB) were used to detect the expression of CSRP2 in CRC tissues and paracancerous tissues. CSRP2 function in CRC was determined by a series of functional tests in vivo and in vitro. WB and immunofluorescence were used to determine the relation between CSRP2 and epithelial-mesenchymal transition (EMT). Co-immunoprecipitation and scanning electron microscopy were used to study the molecular mechanism of CSRP2 in CRC. Results: The CSRP2 expression level in CRC tissues was lower than in adjacent normal tissues and indicated poor prognosis in CRC patients. Functionally, CSRP2 could suppress the proliferation, migration, and invasion of CRC cells in vitro and inhibit CRC tumorigenesis and metastasis in vivo. Mechanistic investigations revealed a physical interaction between CSRP2 and p130Cas. CSRP2 could inhibit the activation of Rac1 by preventing the phosphorylation of p130Cas, thus activating the Hippo signaling pathway, and simultaneously inhibiting the ERK and PAK/LIMK/cortactin signaling pathways, thereby inhibiting the EMT and metastasis of CRC. Rescue experiments showed that blocking the p130Cas and Rac1 activation could inhibit EMT induced by CSRP2 silencing. Conclusion: Our results suggest that the CSRP2/p130Cas/Rac1 axis can inhibit CRC aggressiveness and metastasis through the Hippo, ERK, and PAK signaling pathways. Therefore, CSRP2 may be a potential therapeutic target for CRC.

| S-EPMC7532686 | biostudies-literature

Hippo signaling suppresses tumor cell metastasis via a Yki-Src42A positive feedback loop.

Project description:Metastasis is an important cause of death from malignant tumors. It is of great significance to explore the molecular mechanism of metastasis for the development of anti-cancer drugs. Here, we find that the Hippo pathway hampers tumor cell metastasis in vivo. Silence of hpo or its downstream wts promotes tumor cell migration in a Yki-dependent manner. Furthermore, we identify that inhibition of the Hippo pathway promotes tumor cell migration through transcriptional activating src42A, a Drosophila homolog of the SRC oncogene. Yki activates src42A transcription through direct binding its intron region. Intriguingly, Src42A further increases Yki transcriptional activity to form a positive feedback loop. Finally, we show that SRC is also a target of YAP and important for YAP to promote the migration of human hepatocellular carcinoma cells. Together, our findings uncover a conserved Yki/YAP-Src42A/SRC positive feedback loop promoting tumor cell migration and provide SRC as a potential therapeutic target for YAP-driven metastatic tumors.

| S-EPMC8642408 | biostudies-literature

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