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PP2Ac/STRN4 negatively regulates STING-Type I interferon signaling in tumor associated macrophages [scRNA-seq]

ABSTRACT: STING-Type I interferon (IFN) signaling in myeloid cells plays a critical role in effective antitumor immune responses, but STING agonist as monotherapy has shown limited efficacy in clinical trials. The mechanisms that downregulate STING signaling are not fully understood. Here, we report that Protein phosphatase 2A (PP2A) with its specific B regulatory subunit STRN4 negatively regulated STING-Type I IFN in macrophages. Mice with macrophages PP2A deficiency exhibited reduced tumor progression. The tumor microenvironment showed decreased immunosuppressive and increased IFN-activated macrophages and CD8+ T cells. Mechanistically, we demonstrated that hippo kinase MST1/2 was required for STING activation. STING agonist induced dissociation of PP2A from MST1/2 in normal macrophages, but not in tumor conditioned macrophages. Furthermore, our data showed that STRN4 mediated PP2A binding to and dephosphorylation of hippo kinase MST1/2, resulting in stabilization of YAP/TAZ to antagonize STING activation. In human GBM patients, YAP/TAZ was highly expressed in tumor-associated macrophages but not in non-tumor macrophages. We also demonstrated that PP2A/STRN4 deficiency in macrophages reduced YAP/TAZ expression and sensitized tumor conditioned macrophages to STING stimulation. In summary, we demonstrated that PP2A/STRN4-YAP/TAZ is a previously unappreciated mechanism that mediate immunosuppression in tumor-associated macrophages and targeting PP2A/STRN4-YAP/TAZ axis can sensitize tumors to immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE199247 | GEO | 2023/02/09

REPOSITORIES: GEO

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PP2Ac/STRN4 negatively regulates STING-Type I interferon signaling in tumor associated macrophages [RNA-Seq]

Project description:STING-Type I interferon (IFN) signaling in myeloid cells plays a critical role in effective antitumor immune responses, but STING agonist as monotherapy has shown limited efficacy in clinical trials. The mechanisms that downregulate STING signaling are not fully understood. Here, we report that Protein phosphatase 2A (PP2A) with its specific B regulatory subunit STRN4 negatively regulated STING-Type I IFN in macrophages. Mice with macrophages PP2A deficiency exhibited reduced tumor progression. The tumor microenvironment showed decreased immunosuppressive and increased IFN-activated macrophages and CD8+ T cells. Mechanistically, we demonstrated that hippo kinase MST1/2 was required for STING activation. STING agonist induced dissociation of PP2A from MST1/2 in normal macrophages, but not in tumor conditioned macrophages. Furthermore, our data showed that STRN4 mediated PP2A binding to and dephosphorylation of hippo kinase MST1/2, resulting in stabilization of YAP/TAZ to antagonize STING activation. In human GBM patients, YAP/TAZ was highly expressed in tumor-associated macrophages but not in non-tumor macrophages. We also demonstrated that PP2A/STRN4 deficiency in macrophages reduced YAP/TAZ expression and sensitized tumor conditioned macrophages to STING stimulation. In summary, we demonstrated that PP2A/STRN4-YAP/TAZ is a previously unappreciated mechanism that mediate immunosuppression in tumor-associated macrophages and targeting PP2A/STRN4-YAP/TAZ axis can sensitize tumors to immunotherapy.

2023-02-09 | GSE199251 | GEO

Gene expression profiling of effect of Yap inhibition in a genetically engineered mouse model of hepatocellular carcinoma

Project description:Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC). Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. We show that YAP functions as a rheostat maintaining metabolic specialization, differentiation and quiescence within the hepatocyte compartment. Importantly, treatment with siRNA-lipid nanoparticles (siRNA-LNPs) targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model (mice with liver-specific Mst1/Mst2 double knockout). Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations. Thus, our work reveals Hippo signaling as a key regulator of positional identity of hepatocytes, supports targeting YAP using siRNA-LNPs as a paradigm of differentiation-based therapy, and identifies an HCC subtype potentially responsive to this approach. Mice with liver-specific Mst1/Mst2 double-knockout (Adeno-Cre injected Mst1-/-; Mst2Flox/Flox mice) were monitored for the formation of HCC by ultrasound imaging. Animals were then randomized to be treated by intravenous injection of either siYap-LNPs or siLuciferase-LNPs for a period of 9 days.

2015-03-07 | E-GEOD-65665 | biostudies-arrayexpress

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

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.

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 [DSS_scRNAseq]

2020-06-24 | GSE152369 | GEO

Regulation of gene expression by the Hippo effectors, Taz and Yap, in muscle stem cells

Project description:The Hippo pathway downstream effectors, Yap and Taz, play key roles in cell proliferation and tissue growth, regulating gene expression especially via interaction with Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analysed gene expression changes driven by Taz and compared these to Yap mediated changes to the transcriptome by measurement of gene expression on Affymetrix microarrays. To interrogate overlapping and unique transcriptional changes driven by these Hippo effectors, satellite cell-derived myoblasts were transduced with constitutively active TAZ S89A or YAP S127A retrovirus for 24h or 48h, with empty retrovirus as control. Triplicate microarray analyses of empty vector controls, hYAP1 S127A and TAZ S89A transgenic primary myoblasts were conducted.

2017-06-20 | E-MTAB-5395 | biostudies-arrayexpress

The effect of YAP/TAZ knockdown on the intestinal epithelium

Project description:The Hippo pathway plays a crucial in organ size control during development and tissue homeostasis in adult life. To examine a role for Hippo signaling in the intestinal epithelium, we analyzed gene expression patterns in the mouse intestinal epithelilum transfected with siRNAs or expression plasmids for shRNAs targeting the Hippo pathway effectors, YAP and TAZ. We performed two independent series of experiments (siGFP (n=3) vs siYAP/siTAZ (n=3), and shLacZ (n=1) vs shYAP/shTAZ (n=1)). Control siRNA (siGFP), YAP/TAZ siRNAs, or expression plasmids for control shRNA (shLacZ) or YAP/TAZ shRNAs were introduced into the mouse intestinal epithelium by the newly-developed in vivo transfection method. Four days after transfection, intestinal epithelial cells were isolated from the tissues and total RNA was extracted.

2014-07-18 | E-GEOD-45155 | biostudies-arrayexpress

Transcriptional targets of Hippo signaling in mammalian cells

Project description:The Hippo pathway is an emerging signaling cascade involved in the regulation of organ size control. It consists of evolutionally conserved protein kinases that are sequentially phosphorylated and activated. The active Hippo pathway subsequently phosphorylates a transcription coactivator, YAP, which precludes its nuclear localization and transcriptional activation. Identification of transcriptional targets of YAP in diverse cellular contexts is therefore critical to the understanding of the molecular mechanisms in which the Hippo pathway restricts tissue growth. We used microarrays to profile the gene expression patterns upon acute siRNA knockdown of Hippo pathway components in multiple mammalian cell lines and identified a set of genes representing immediate transcriptional targets of the Hippo/Yap signaling pathway. Three mammalian cell lines (HEK293T, HepG2, HaCaT) were transfected with scramble siRNA controls or siRNAs against NF2 and LATS2, two core components of the Hippo pathway, simultaneously. Total RNAs were harvested four days after transfection to reveal the gene expression pattern unsing microarry. YAP and TAZ siRNAs were also transfected along with NF2 and LATS2 siRNAs to identify YAP/TAZ-dependent transcriptional targets upon loss of NF2/LATS2.

2013-12-31 | E-GEOD-49384 | biostudies-arrayexpress

A novel irreversible TEAD inhibitor, SWTX-143, blocks the Hippo pathway and causes tumor regression in preclinical mesothelioma models [SubQ]

Project description:The Hippo pathway and its downstream effectors, the YAP and TAZ transcriptional coactivators, are deregulated in multiple different types of human cancer and are required for cancer cell phenotypes in vitro and in vivo, while largely dispensable for tissue homeostasis in adult mice. YAP/TAZ and their partner transcription factors, the TEAD1-4 factors, are therefore promising anti-cancer targets. Due to frequent YAP/TAZ hyperactivation caused by mutations in the Hippo pathway components NF2 and Lats2, mesothelioma is one of the prime cancer types predicted to be responsive to YAP/TAZ-TEAD inhibitor treatment. Mesothelioma is a devastating disease for which currently no effective treatment options exist. Here, we describe a novel covalent YAP/TAZ-TEAD inhibitor, SWTX-143, that binds to the palmitoylation pocket of all TEAD isoforms. SWTX-143 caused irreversible and specific inhibition of the transcriptional activity of YAP/TAZ-TEAD in Hippo-mutant tumor cell lines. More importantly, YAP/TAZ-TEAD inhibitor treatment caused strong mesothelioma regression in human subcutaneous xenograft models and in an orthotopic mesothelioma mouse model. Finally, SWTX-143 also selectively impaired the growth of NF2-mutant kidney cancer cell lines, suggesting that the exquisite sensitivity of mesothelioma to these YAP/TAZ-TEAD inhibitors can be extended to other tumor types with aberrations in Hippo signaling. In brief, we describe a novel and specific YAP/TAZ-TEAD inhibitor that has great potential to treat multiple Hippo-mutant solid tumor types.

2023-10-04 | GSE222962 | GEO

A novel irreversible TEAD inhibitor, SWTX-143, blocks the Hippo pathway and causes tumor regression in preclinical mesothelioma models [Invitro]

2023-10-04 | GSE222960 | GEO

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