Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA241326 | ENA |
REPOSITORIES: ENA
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Project description:Background: PTEN loss contributes to the development of many cancers and is associated with both hepatocellular carcinoma and cholangiocarcinoma. The pathogenesis of these malignancies is unclear, but they are speculated to arise from common cellular origins. We explored the influence of secondary effects, like hypoxia signaling, through co-deletion of Pten and Vhl in a murine model.Methods: We used a CreER-linked keratin 18 mouse model to conditionally delete Pten, Vhl or both, evaluating the resultant tumors by histology and gene expression microarray. A cohort of human cholangiocarcinoma samples was evaluated for relationships between HIF-1a expression and clinical outcomes.Results: Both Pten deletion genotypes developed liver tumors, but with differing phenotypes. Pten deletion alone led to large, invasive tumors with widespread hepatosteatosis. Co-deletion of Pten and Vhl resulted in low tumor burden and reduced steatosis. Microarray analysis divided mouse tumors’ respective genotypes by gene expression. This gene expression profile grouped a human tumor cohort according to histologic type with the Pten deletion signature aligning with hepatocellular carcinoma, whereas the Pten; Vhl deletion signature associated with cholangiocarcinomas. In a human cholangiocarcinoma cohort, we observed correlation between HIF-1a expression and overall survival.Conclusions: Pten deletion leads to tumor formation and steatosis in mouse livers. Co-deletion of Vhl and Pten resulted in lower tumor burden with gene expression profiling suggesting a switch from hepatocellular expression features to an expression profile more consistent with cholangiocarinoma. A possible relation between HIF-1a expression and increased overall survival in human cholangiocarcinoma suggests that hypoxia signaling influences tumor phenotype. reference x sample
2014-10-31 | E-GEOD-55874 | biostudies-arrayexpress
Project description:Background: PTEN loss contributes to the development of many cancers and is associated with both hepatocellular carcinoma and cholangiocarcinoma. The pathogenesis of these malignancies is unclear, but they are speculated to arise from common cellular origins. We explored the influence of secondary effects, like hypoxia signaling, through co-deletion of Pten and Vhl in a murine model.Methods: We used a CreER-linked keratin 18 mouse model to conditionally delete Pten, Vhl or both, evaluating the resultant tumors by histology and gene expression microarray. A cohort of human cholangiocarcinoma samples was evaluated for relationships between HIF-1a expression and clinical outcomes.Results: Both Pten deletion genotypes developed liver tumors, but with differing phenotypes. Pten deletion alone led to large, invasive tumors with widespread hepatosteatosis. Co-deletion of Pten and Vhl resulted in low tumor burden and reduced steatosis. Microarray analysis divided mouse tumors’ respective genotypes by gene expression. This gene expression profile grouped a human tumor cohort according to histologic type with the Pten deletion signature aligning with hepatocellular carcinoma, whereas the Pten; Vhl deletion signature associated with cholangiocarcinomas. In a human cholangiocarcinoma cohort, we observed correlation between HIF-1a expression and overall survival.Conclusions: Pten deletion leads to tumor formation and steatosis in mouse livers. Co-deletion of Vhl and Pten resulted in lower tumor burden with gene expression profiling suggesting a switch from hepatocellular expression features to an expression profile more consistent with cholangiocarinoma. A possible relation between HIF-1a expression and increased overall survival in human cholangiocarcinoma suggests that hypoxia signaling influences tumor phenotype.
2014-10-31 | GSE55874 | GEO
Project description:<p>Cancer cells can always be unexpected rescued from desperate environment by mounting adaptive responses to resolve the arising cellular stress. The dynamic stress granules (SGs) assembly and metabolic reprogramming play crucial roles in maintaining cellular growth and homeostasis. However, the mechanisms underlying their interaction remain elusive. Here we screened RIOK1 is highly expressed in liver cancer tissues and is transactivated by NRF2 under stressful conditions. Mechanistically, the oncogenic phenotype observed in hepatocellular carcinoma (HCC) cells is associated with the capacity of RIOK1 to undergo liquid-liquid phase separation. The non-enzymatic regulation of IGF2BP1 tyrosine phosphorylation by RIOK1 contributes to incorporating RIOK1/IGF2BP1/G3BP1 into stress granules which concurrently sequester PTEN mRNA. The decrease in PTEN translation concomitantly activates the pentose phosphate pathway to resolve stress and confer cytoprotection. Additionally, chidamide downregulates RIOK1 expression and enhances the efficacy of TKIs, presenting a promising therapeutic strategy for HCC treatment.</p>
2025-02-26 | MTBLS11963 | MetaboLights
Project description:CRISPR/Cas9 mutation of Vhl, Pten, Trp53
| PRJNA272478 | ENA
Project description:Dysregulation of the PI3K/AKT pathway is a common occurrence in ovarian carcinomas. Loss of the tumour suppressor PTEN in high-grade serous ovarian carcinoma (HGSOC) is associated with a patient subgroup with poor prognosis. The cellular mechanisms of how PTEN loss contributes to HGSOC are largely unknown. We utilise long-term time-lapse imaging of HGSOC spheroids coupled to a machine learning approach to classify the phenotype of PTEN loss. PTEN deficiency does not affect proliferation but rather induces PI(3,4,5)P3-rich and -dependent membrane protrusions into the extracellular matrix (ECM), resulting in a collective invasion phenotype. We identify the small GTPase ARF6 as a crucial vulnerability upon PTEN loss. Through a functional proteomic CRISPR screen of ARF6 interactors, we identify the ARF GTPase-activating protein (GAP) AGAP1 and the ECM receptor β1-integrin as key ARF6 interactors regulating the PTEN loss-associated invasion phenotype. ARF6 functions to promote invasion by controlling the recycling of internalised, active β1-integrin complexes to maintain invasive activity into the ECM. The expression of the ARF6-centred complex in HGSOC patients is inversely associated with outcome, allowing identification of patient groups with improved versus poor outcome. ARF6 may represent a new therapeutic vulnerability in PTEN-depleted HGSOC tumours.
2023-07-11 | PXD038305 | Pride
Project description:The PTEN tumor suppressor controls cell death and survival by regulating functions of various molecular targets. Whilst the role of PTEN lipid-phosphatase activity on PtdIns(3,4,5)P3 and inhibition of PI3K pathway is well characterized, the biological relevance of PTEN protein-phosphatase activity remains undefined. Using knock-in (KI) mice harbouring cancer-associated and functionally relevant missense mutations, we show that although loss of PTEN lipid-phosphatase function cooperates with oncogenic PI3K to promote rapid mammary tumorigenesis, the additional loss of PTEN protein-phosphatase activity triggered an extensive cell death response evident in early and advanced mammary tumors. Omics and drug-targeting studies revealed that PI3Ks act to reduce glucocorticoid receptor (GR) levels, which are rescued by loss of PTEN protein-phosphatase activity to restrain cell survival. The dual regulation of GR by PI3K and PTEN functions as a rheostat that can be exploited for the treatment of PTEN-loss driven cancers.
2020-10-15 | PXD016184 | Pride
Project description:PTEN, a well-known tumor suppressor, negatively regulates the PI3K-AKT signaling pathway. Its loss is prevalent across various cancer types and leads to significant changes in cellular signaling networks. In this study, we investigate the effects of PTEN loss on both canonical PI3K-AKT and noncanonical tyrosine kinase pathways in MCF10A PTEN knockout (KO) cells. Through quantitative proteomics and phosphoproteomics, we identified substantial changes in protein and phosphorylation profiles, including key signaling regulators such as EphA2, Src, and MEK-ERK1/2. Our findings reveal that PTEN loss not only activates PI3K-AKT signaling but also elevates tyrosine kinase signaling, with Src kinase playing a crucial role in upregulating EphA2, an RTK implicated in tumor progression. Interestingly, inhibition of AKT alone did not consistently reduce EphA2 levels, highlighting an AKT-independent mechanism of EphA2 regulation via Src in PTEN-deficient cells. We demonstrated that combined targeting of AKT and Src pathways using Capivasertib (AKT inhibitor) and Dasatinib (Src inhibitor) significantly suppressed proliferation and induced apoptosis in PTEN-deficient breast and endometrial cancer cell lines, with notable synergy observed in patient-derived xenograft (PDX) models. These results suggest that dual inhibition of AKT and Src could provide a promising therapeutic approach for PTEN-deficient cancers, addressing resistance limitations associated with AKT inhibition alone and improving therapeutic efficacy. This study underscores the complex regulatory mechanisms involving PTEN and highlights new possibilities for targeted combination therapies in cancers with PTEN loss.
2025-12-15 | PXD057520 | Pride
Project description:Inflammation has a causal role in many cancers. In prostate cancers, epidemiological data suggest a link between prostatitis and subsequent cancer development, but a proof for this concept in a tumor model has been lacking. A constitutively active version of the IkappaB kinase 2 (IKK2), the molecule activated by a plethora of inflammatory stimuli, was expressed specifically in the prostate epithelium. Signaling of the IKK2/NF-kappaB axis was insufficient for transformation of prostate tissue. However, while PTEN+/- epithelia exhibited intraepithelial neoplasias only recognizable by nuclear alterations, additional IKK2 activation led to an increase in tumor size and formation of cribriform structures and to a fiber increase in the fibroblastic stroma. This phenotype was coupled with inflammation in the prostate gland characterized by infiltration of granulocytes and macrophages. Molecular characterization of the tissues showed a specific loss of smooth muscle markers as well as expression of chemokines attracting immune cells. Isolation of epithelial and stromal cells showed differential chemokine expression by these cells. Correlation studies showed the inflammatory phenotype coupled to loss of smooth muscle in infiltrated glands, but maintenance of the phenotype in glands where inflammation had decreased. Despite the loss of the smooth muscle barrier, tumors were not invasive in a stable genetic background. Data mining revealed that smooth muscle markers are downregulated in human prostate cancers and literature data show that loss of these markers in primary tumors is associated with subsequent metastasis. Our data show that loss of smooth muscle and invasiveness of the tumor are not coupled. Thus, inflammation during early steps of tumorigenesis can lead to increased tumor size and a potential change in the subsequent metastatic potential, but the tumor requires an additional transformation to become a carcinoma. Microarray analysis was used to determine expression differences in lateral prostates from mice with PTEN+/- IKK2ca/ca epithelium (n=3) compared to lateral prostates from mice with PTEN+/- epithelium (n=3).
2011-07-01 | E-GEOD-26410 | biostudies-arrayexpress
Project description:Intrahepatic cholangiocarcinoma (ICC) is known to have a poor prognosis among primary liver cancers. We created a mouse model of cholangiocarcinogenesis by specifically deleting Pten and Traf3 in the liver. RNA sequence was performed with RNA extracted from the liver of mice lacking liver-specific Pten and Traf3.
2022-03-31 | GSE178418 | GEO
Project description:Cancers arising from dysregulation of generally operative signaling pathways are commonly tissue specific, but the mechanisms underlying this paradox are poorly understood. Based on striking cell-type specificity, we postulated that these mechanisms must operate very early in cancer development and set out to study them in a model of von Hippel Lindau disease. Biallelic mutation of the VHL ubiquitin ligase leads to constitutive activation of hypoxia inducible factors HIF1A and HIF2A and is often a truncal event in clear cell renal carcinoma. We used an oncogenic tagging strategy in which VHL-mutant cells are marked by tdTomato, enabling their observation, retrieval, and analysis early after VHL-inactivation. Our findings reveal markedly different consequences of HIF1A and HIF2A activation, but that both contribute to renal cell-type specific consequences of VHL-inactivation in the kidney. Early involvement of HIF2A in promoting proliferation within proximal tubular epithelium supports therapeutic targeting of HIF2A early in VHL disease.
2025-08-15 | GSE282887 | GEO