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TP53 missense-specific transcriptional plasticity drives resistance against cell cycle inhibitors in pancreatic cancer [ChIP-Seq]

ABSTRACT: TP53 missense-specific transcriptional plasticity drives resistance against cell cycle inhibitors in pancreatic cancer [ChIP-Seq]

PROVIDER: PRJNA1231433 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32568286.fastq.gz	Fastqsanger.gz
	SRR32568287.fastq.gz	Fastqsanger.gz
	SRR32568288.fastq.gz	Fastqsanger.gz
	SRR32568289.fastq.gz	Fastqsanger.gz

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TP53 missense-specific transcriptional plasticity drives resistance against cell cycle inhibitors in pancreatic cancer [ChIP-Seq]

Project description:In ~70% of pancreatic ductal adenocarcinoma (PDAC) patients, the TP53 gene acquires gain-of-function (GOF) mutations leading to rapid disease progression. Specifically, missense p53 (misp53) GOF mutations associate with therapy resistance and worse clinical outcomes. However, the molecular functions of distinct misp53 mutants in plasticity and therapy response remain unclear. Integrating multi-center patients’ data and multi-omics, we report that the misp53R273H/C mutant is associated with cell-cycle progression and a basal-like state compared to the misp53R248W/Q mutant. Loss of misp53R273H/C decreased tumor growth and liver metastasis while prolonging survival in preclinical models. We found that misp53R273H/C specifically regulates the Rb/DREAM axis involved in cell cycle regulation. Notably, a clinical CDK4/6 inhibitor specifically reduced misp53R273H/C mutant expression. However, it triggered MAPK/ERK-mediated resistance mechanisms, enhancing cell survival and resistance to CDK4/6 inhibitors. Combining MAPK/ERK and CDK4/6 inhibitors reduced misp53R273H/C-associated oncogenic functions. Thus, distinct misp53 mutants show unique cell-intrinsic plasticity, therapeutic vulnerabilities, and resistance mechanisms.

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TP53 missense-specific transcriptional plasticity drives resistance against cell cycle inhibitors in pancreatic cancer [RNA-Seq]

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TP53 missense-specific transcriptional plasticity drives resistance against cell cycle inhibitors in pancreatic cancer

Project description:TP53 missense-specific transcriptional plasticity drives resistance against cell cycle inhibitors in pancreatic cancer

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TP53 missense-specific transcriptional plasticity drives resistance against cell cycle inhibitors in pancreatic cancer [RNA-Seq]

Project description:TP53 missense-specific transcriptional plasticity drives resistance against cell cycle inhibitors in pancreatic cancer [RNA-Seq]

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TP53 missense-specific transcriptional plasticity drives resistance against cell cycle inhibitors in pancreatic cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-03-05 | GSE291036 | GEO

TMPRSS2-ERG suppresses PTEN/TP53 alteration-induced cancer lineage plasticity

Project description:Lineage plasticity is a major mechanism driving prostate cancer progression and antiandrogen therapy resistance. Deletions or mutations in phosphatase and tensin homolog (PTEN) and TP53 tumor suppressor genes have been linked to lineage plasticity in prostate cancer. Fusion-driven overexpression of the E-twenty-six transformation specific (ETS)-related gene (ERG), encoding an oncogenic transcription factor, is observed in approximately 50% of all prostate cancers, yet its role in prostate cell lineage determination remains elusive. Here we demonstrate that transgenic expression of prostate cancer-associated ERG blocks Pten and Trp53 mutation-induced decreased expression of Ar and its downstream target genes and loss of luminal epithelial cell identity in the mouse prostate. Integrative analyses of ERG chromatin-immunoprecipitation sequencing (ChIP-seq) and transcriptome data show that ERG suppresses expression of a subset of cell cycle-promoting genes and RB phosphorylation, which in turn causes repression of E2F1-mediated expression of non-epithelial lineage genes. Xenograft studies show that PTEN/TP53 double mutated prostate tumors are responsive to the cyclin-dependent kinase 4 or 6 (CDK4/6) inhibitor palbociclib, but resistant to the AR inhibitor enzalutamide, while ERG/PTEN/TP53 triple-mutated prostate tumors behave completely opposite. Our studies identify ERG and the repressed cell cycle gene signature as intrinsic inhibitors of PTEN/TP53 double mutation-elicited lineage plasticity in prostate cancer. Our findings also suggest that ERG fusion can be utilized as a biomarker to guide the treatment of PTEN/TP53-mutated, RB1-intact prostate cancer with either antiandrogen or anti-CDK4/6 therapies.

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Project description:TP53, encoding for the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, have remained enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We generated isogenic human leukemia cell lines of the most common TP53 missense mutations using CRISPR/Cas9. Functional, DNA binding, and transcriptional analyses revealed loss-of-function (LOF) without GOF effects of missense mutations. Comprehensive mutational scanning of p53 single amino acid variants demonstrated that DNA-binding domain missense variants exert dominant-negative effects (DNE). In mice, DNE of p53 missense variants confer a selective advantage on hematopoietic cells upon DNA damage in vivo. Clinical outcomes in acute myeloid leukemia patients showed no evidence of GOF for TP53 missense mutations. These findings establish dominant-negativity as the primary unit of selection for TP53 missense mutations in myeloid malignancies.

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2023-10-06 | GSE239706 | GEO

Genome-wide binding of wild-type and missense mutant p53 in isogenic human acute myeloid leukemia (AML) cell lines

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Genome-wide binding of wild-type p53 and R248Q missense mutant variants in isogenic human acute myeloid leukemia (AML) cell lines

Project description:TP53, encoding for the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, have remained enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We generated isogenic human leukemia cell lines of the most common TP53 missense mutations using CRISPR/Cas9. Functional, DNA binding, and transcriptional analyses revealed loss-of-function (LOF) without GOF effects of missense mutations. Comprehensive mutational scanning of p53 single amino acid variants demonstrated that DNA-binding domain missense variants exert dominant-negative effects (DNE). The precise functional and molecular mechanisms of the DNE have remained elusive. Using a variety of novel model systems including CRISPR-edited human isogenic cell lines, transcriptional reporter cell lines, and targeted protein degradation assays combined with functional and molecular analyses we functionally characterize the DNE and demonstrate that formation of heterotetramers between R248Q and WT p53 impairs proper WT p53 functionality by preventing DNA binding and subsequent target gene transactivation.

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