YAP1 oncogene is a context-specific driver for pancreatic ductal adenocarcinoma
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ABSTRACT:
PROVIDER: PRJNA559899 | ENA |
REPOSITORIES: ENA
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Project description:Transcriptomic profiling classifies pancreatic ductal adenocarcinoma (PDAC) into several molecular subtypes with distinctive histological and clinical characteristics. However, little is known about the molecular mechanisms that define each subtype and how this correlates with clinical outcome. Mutant KRAS is the most prominent driver in PDAC, present in over 90% of tumors, but the dependence of tumors on oncogenic KRAS signaling varies between subtypes. In particular, squamous subtype PDACs are relatively independent of oncogenic KRAS signaling and typically display much more aggressive clinical behavior versus progenitor subtype PDACs. Here, we identified that YAP1 activation is enriched in the squamous subtype and associated with poor prognosis. Activation of YAP1 in progenitor subtype cancer cells profoundly enhanced malignant phenotypes and transformed progenitor subtype cells into squamous subtype. Conversely, depletion of YAP1 specifically suppressed tumorigenicity of squamous subtype PDAC tumors. Mechanistically, we uncovered a significant positive correlation between WNT5A expression and the YAP activation signature, and we demonstrated that WNT5A overexpression led to YAP activation and recapitulated YAP1-dependent but but Kras-independent phenotype of tumor progression and maintenance. Thus, our study identifies YAP1 oncogene as a major driver of squamous subtype PDAC and uncovers the role of WNT5A to drive PDAC malignancy via activation of the YAP pathway.
2019-10-01 | GSE135754 | GEO
Project description:Transcriptomic profiling classifies pancreatic ductal adenocarcinoma (PDAC) into several molecular subtypes with distinctive histological and clinical characteristics. However, little is known about the molecular mechanisms that define each subtype and their correlation with clinical outcome. Mutant KRAS is the most prominent driver in PDAC, present in over 90% of tumors, but the dependence of tumors on oncogenic KRAS signaling varies between subtypes. In particular, the squamous subtype is relatively independent of oncogenic KRAS signaling and typically displays much more aggressive clinical behavior versus the progenitor subtype. Here, we identified that yes-associated protein 1 (YAP1) activation is enriched in the squamous subtype and associated with poor prognosis. Activation of YAP1 in progenitor subtype cancer cells profoundly enhanced malignant phenotypes and transformed progenitor subtype cells into squamous subtype. Conversely, depletion of YAP1 specifically suppressed tumorigenicity of squamous subtype PDAC cells. Mechanistically, we uncovered a significant positive correlation between WNT5A expression and YAP1 activity in human PDAC and demonstrated that WNT5A overexpression led to YAP1 activation and recapitulated a YAP1-dependent but Kras-independent phenotype of tumor progression and maintenance. Thus, our study identifies YAP1 oncogene as a major driver of squamous subtype PDAC and uncovers the role of WNT5A in driving PDAC malignancy through activation of the YAP pathway.
| S-EPMC6948828 | biostudies-literature
Project description:The incidence of many human cancers differs according to sex, but little is known about the interplay between oncogenic events and sex as a variable in tumorigenesis. Here we report that the oncogene Yap1 is sexually dimorphic in medulloblastoma progression and immune suppression. We show that Yap1 promotes stemness and blocks differentiation in sonic hedgehog (SHH)-subtype medulloblastoma by at least two distinct but complementary molecular mechanisms to regulate the RNA expression and protein functions of Sox2, Atoh1, NeuroD1, and Zic1/2. Yap1 also promotes an immune suppressive tumor microenvironment by directly regulating Csf1, Igf1, and Igfbp3 transcription and modulating IL6-JAK-STAT3, TNFR1, TGF-β, and CCL5 immune pathways. Notably, Yap1 function is more critical in males and this is evolutionarily conserved: genes downstream of YAP1 identified in mouse models stratify male but not female medulloblastoma patient survival. In summary, we demonstrate a sex-based function for an oncogene, underscoring the critical need to incorporate sex as a variable in cancer mechanism and clinical response studies, particularly those involving YAP1
2026-02-02 | GSE223112 | GEO
Project description:The incidence of many human cancers differs according to sex, but little is known about the interplay between oncogenic events and sex as a variable in tumorigenesis. Here we report that the oncogene Yap1 is sexually dimorphic in medulloblastoma progression and immune suppression. We show that Yap1 promotes stemness and blocks differentiation in sonic hedgehog (SHH)-subtype medulloblastoma by at least two distinct but complementary molecular mechanisms to regulate the RNA expression and protein functions of Sox2, Atoh1, NeuroD1, and Zic1/2. Yap1 also promotes an immune suppressive tumor microenvironment by directly regulating Csf1, Igf1, and Igfbp3 transcription and modulating IL6-JAK-STAT3, TNFR1, TGF-β, and CCL5 immune pathways. Notably, Yap1 function is more critical in males and this is evolutionarily conserved: genes downstream of YAP1 identified in mouse models stratify male but not female medulloblastoma patient survival. In summary, we demonstrate a sex-based function for an oncogene, underscoring the critical need to incorporate sex as a variable in cancer mechanism and clinical response studies, particularly those involving YAP1
2026-02-02 | GSE223111 | GEO
Project description:The incidence of many human cancers differs according to sex, but little is known about the interplay between oncogenic events and sex as a variable in tumorigenesis. Here we report that the oncogene Yap1 is sexually dimorphic in medulloblastoma progression and immune suppression. We show that Yap1 promotes stemness and blocks differentiation in sonic hedgehog (SHH)-subtype medulloblastoma by at least two distinct but complementary molecular mechanisms to regulate the RNA expression and protein functions of Sox2, Atoh1, NeuroD1, and Zic1/2. Yap1 also promotes an immune suppressive tumor microenvironment by directly regulating Csf1, Igf1, and Igfbp3 transcription and modulating IL6-JAK-STAT3, TNFR1, TGF-β, and CCL5 immune pathways. Notably, Yap1 function is more critical in males and this is evolutionarily conserved: genes downstream of YAP1 identified in mouse models stratify male but not female medulloblastoma patient survival. In summary, we demonstrate a sex-based function for an oncogene, underscoring the critical need to incorporate sex as a variable in cancer mechanism and clinical response studies, particularly those involving YAP1
2026-02-02 | GSE223114 | GEO
Project description:The incidence of many human cancers differs according to sex, but little is known about the interplay between oncogenic events and sex as a variable in tumorigenesis. Here we report that the oncogene Yap1 is sexually dimorphic in medulloblastoma progression and immune suppression. We show that Yap1 promotes stemness and blocks differentiation in sonic hedgehog (SHH)-subtype medulloblastoma by at least two distinct but complementary molecular mechanisms to regulate the RNA expression and protein functions of Sox2, Atoh1, NeuroD1, and Zic1/2. Yap1 also promotes an immune suppressive tumor microenvironment by directly regulating Csf1, Igf1, and Igfbp3 transcription and modulating IL6-JAK-STAT3, TNFR1, TGF-β, and CCL5 immune pathways. Notably, Yap1 function is more critical in males and this is evolutionarily conserved: genes downstream of YAP1 identified in mouse models stratify male but not female medulloblastoma patient survival. In summary, we demonstrate a sex-based function for an oncogene, underscoring the critical need to incorporate sex as a variable in cancer mechanism and clinical response studies, particularly those involving YAP1
2026-02-02 | GSE223113 | GEO
Project description:Structural variants drive context dependent oncogene activation in cancer
| PRJNA613064 | ENA
Project description:The transcriptional co-activator YAP1 oncogene is the downstream effector of the Hippo pathway, which regulates tissue homeostasis, organ size, regeneration and tumorigenesis. Multiple cancers are dependent on sustained expression of YAP1 for cell proliferation, survival and tumorigenesis, but the molecular basis of this oncogene dependency is not well understood. To identify genes that can functionally substitute for YAP1, we performed a genome-scale genetic rescue screen in YAP1-dependent colon cancer cells expressing an inducible YAP1-specific shRNA. We found that the transcription factor PRDM14 rescued cell proliferation and tumorigenesis upon YAP1 suppression in YAP1-dependent cells, xenografts, and colon cancer organoids. YAP1 and PRDM14 individually activated the transcription of calmodulin 2 (CALM2) and a glucose transporter SLC2A1 upon YAP1 suppression; and CALM2 or SLC2A1 expression was required for the rescue of YAP1 suppression. Together, these findings implicate PRDM14-mediated transcriptional upregulation of CALM2 and SLC2A1 as key components of oncogenic YAP1 signaling and dependency.
2022-01-05 | GSE182432 | GEO
Project description:Tumors acquire somatic DNA copy number aberrations, leading to activation of oncogenes and inactivation of tumor suppressors. Many studies have focused on the analysis of single copy number aberrations and associated driver genes, but few studies have performed combinatorial analyses. We propose a genome-wide scoring framework to find mutually exclusive gains and losses. Mutually exclusive copy number aberrations can identify genes whose oncogenic function is redundant, either by functioning in the same pathway or in a parallel pathway. As one gene is aberrated the selective pressure for its partner is alleviated which leads to a mutually exclusive perturbation pattern. In a dataset of mouse models for invasive lobular carcinoma we found three mutually exclusive DNA amplifications, containing several well-known oncogenes: the Met proto-oncogene on chromosome 6, the cluster of Birc2, Birc3 and Yap1 genes on chromosome 9, and Nras on chromosome 3. Furthermore, gene expression or protein expression of these genes correlates very well with copy number data indicating that they are the target of the amplification. Although homologous amplifications in human tumors are rare, the mutual exclusivity of MET, BIRC/YAP1 and NRAS is maintained in a variety of cancer types. This suggests a novel function for YAP1 in the mitogen-activated signaling pathway by association with MET and NRAS, known players in this pathway. This function is independent to the propensity of YAP1 to cause Epithelial-to-Mesenchymal transition. aCGH data of 67 mouse mammary tumors from K14-Cre and WAP-Cre driven P53-F/F;Cdh1-F/F animals - tumor DNA hybridized against same-animal splenic DNA
2011-12-01 | E-GEOD-28432 | biostudies-arrayexpress
Project description:We investigate the dependence of human malignant pleural mesothelioma on a functional YAP1-TEAD transcription factor complex to maintain fully established tumors in vivo. We show that, in a dysfunctional Hippo genetic background, downregulation of YAP1 by shRNA results in modulation of YAP1/TEAD-dependent gene expression and regression of established tumor xenografts. Our data demonstrate that, in the context of a mutated Hippo pathway, YAP1 activity is essential to maintain the growth of mesothelioma cells in vivo, thus validating the concept of inhibiting the activated YAP1/TEAD complex for the treatment of malignant pleural mesothelioma patients.
2022-02-17 | GSE196672 | GEO