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Transcriptional control of subtype switching ensures adaptation and growth of pancreatic cancer

ABSTRACT: Transcriptional control of subtype switching ensures adaptation and growth of pancreatic cancer

PROVIDER: PRJNA543003 | ENA |

REPOSITORIES: ENA

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Transcriptional control of subtype switching ensures adaptation and growth of pancreatic cancer

Project description:Purpose: The goal of this study is to determine whether ectopic expression of the GLI2 transcription factor in the human pancreatic cancer cell line, YAPC is sufficient to cause gene expression changes associated with a EMT switch. Methods: RNA was isolated from YAPC cells engineered to express a doxycycline inducible cassette for ectopic expression of GLI2 following treatment with 1ug/ml of Dox for 6 days. Control YAPC cells expressing an "empty vector" dox inducible cassette were similarly treated for 6 days with 1ug/u Dox and RNA was collected. Three biologically destinct replicates were submitted for library preparation and RNA-sequencing on an Illumina hiseq 2000. The sequence reads that passed quality filters were analyzed at the transcript level using TopHat followed by Cufflinks. qRT–PCR validation was performed using SYBR Green assays Results: RNA-seq data confirmed stable over-expression of GLI2 in the YAPC-rtta-GLI2 cells and not in the EV control cells treated with Dox. Target genes of interest were validated by qRT–PCR. RNA-seq data had a linear relationship with qRT–PCR for all target genes tested. Gene set enrichment analysis of differentially expressed genes showed enrichment of EMT associated pathways which was further validated using functional assays. In addition a statistically significant alteration in SPP1 transcript was discovered in GLI2 overexpressing cells which formed the basis of ongoing experiments in the study. Conclusions: Our data support a role for GLI2 in regulation of genes associated with basal-like subtype switching including SPP1

2019-05-16 | GSE131222 | GEO

Transcriptional control of subtype switching ensures adaptation and growth of pancreatic cancer.

Project description:Pancreatic ductal adenocarcinoma (PDA) is a heterogeneous disease comprised of a basal-like subtype with mesenchymal gene signatures, undifferentiated histopathology and worse prognosis compared to the classical subtype. Despite their prognostic and therapeutic value, the key drivers that establish and control subtype identity remain unknown. Here, we demonstrate that PDA subtypes are not permanently encoded, and identify the GLI2 transcription factor as a master regulator of subtype inter-conversion. GLI2 is elevated in basal-like PDA lines and patient specimens, and forced GLI2 activation is sufficient to convert classical PDA cells to basal-like. Mechanistically, GLI2 upregulates expression of the pro-tumorigenic secreted protein, Osteopontin (OPN), which is especially critical for metastatic growth in vivo and adaptation to oncogenic KRAS ablation. Accordingly, elevated GLI2 and OPN levels predict shortened overall survival of PDA patients. Thus, the GLI2-OPN circuit is a driver of PDA cell plasticity that establishes and maintains an aggressive variant of this disease.

| S-EPMC6538376 | biostudies-literature

ASCL1: a pioneer factor that induces subtype switching and characterizes adrenergic neuroblastoma

Project description:Neuroblastoma is an embryonic malignancy originating from early nerve cells. Neuroblastoma retains plasticity, interconverting between the mesenchymal (MES) and adrenergic (ADRN) states, which are controlled by different sets of transcription factors forming the core regulatory circuit (CRC). However, their functional roles and cooperative mechanisms in neuroblastoma pathogenesis are poorly understood. Here, we demonstrate that overexpression of ASCL1 in MES neuroblastoma cells opens closed chromatin at the promoters of key ADRN genes, accompanied by epigenetic activation and establishment of enhancer-promoter interactions, thereby initiating subtype switching. ASCL1 inhibits the TGFb-SMAD2/3 pathway but activates the BMP-SMAD1-ID3/4 pathway, serving as negative feedback to balance the function of ASCL1-TCF12 dimers. ASCL1 and other ADRN CRC members potentiate each other’s activity, increasing the expression of the original targets and inducing a new set of genes, thereby promoting conversion to ADRN neuroblastoma. Thus, via its pioneer factor function, ASCL1 serves as a master regulator that characterizes ADRN neuroblastoma.

2023-12-08 | PXD037670 | Pride

White-Opaque Switching in Natural MTLa/alpha Isolates of Candida albicans: Evolutionary Implications for Roles in Host Adaptation, Pathogenesis and Sex

Project description:The discovery of white-opaque switching in natural MTLa/alpha isolates of Candida albicans sheds new light on the evolution of phenotypic plasticity and host adaptation. Comparing gene expression of white and opaque cells of a MTL a/alpha strain

2013-04-01 | E-GEOD-43938 | biostudies-arrayexpress

White-Opaque Switching in Natural MTLa/alpha Isolates of Candida albicans: Evolutionary Implications for Roles in Host Adaptation, Pathogenesis and Sex

Project description:The discovery of white-opaque switching in natural MTLa/alpha isolates of Candida albicans sheds new light on the evolution of phenotypic plasticity and host adaptation.

2013-04-01 | GSE43938 | GEO

Adaptation to an acid microenvironment promotes pancreatic cancer organoid growth and drug resistance [acid]

Project description:We investigated transcriptomic changes in pancreatic ductal organoids under adaptation to an acidic extracellular environment.

2024-06-04 | GSE218173 | GEO

H1N1 subtype

Project description:H1N1 subtype

| PRJNA477707 | ENA

KDM6A Epigenetically Regulates Subtype Plasticity in Small Cell Lung Cancer

Project description:Using a CRISPR-based autochthonous SCLC GEMM to study the consequences of KDM6A/UTX inactivation, we found that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumors with open chromatin at the NEUROD1 promoter that express both ASCL1 and NEUROD1. Mechanistically, KDM6A binds and maintains ASCL1 target genes in an active chromatin state with its loss increasing H3K27me3 near their promoters leading to a cell state that is primed for ASCL1 to NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides a novel autochthonous SCLC GEMM to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs

2023-06-08 | GSE211242 | GEO

KDM6A Epigenetically Regulates Subtype Plasticity in Small Cell Lung Cancer

2023-06-08 | GSE211165 | GEO

Expression profiling of budding cells in colorectal cancer suggests an EMT-like phenotype and molecular subtype switching

Project description:Tumour buds undergo phenotype switching while detaching from the main tumour, as they acquire more migratory characteristics and tend to stop proliferating. Simultaneously, an EMT-like signature is observed in the tumour buds under the form of active WNT, TGF and receptor tyrosine kinase signalling. In addition, FOXA2 and RUNX2 well known transcription factors in other cancer types were also differentially expressed in the buds compared to the main tumour mass, hinting at the potential role in tumour budding and initiation of metastasis in colorectal cancer.

2017-02-04 | E-MTAB-4065 | biostudies-arrayexpress

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