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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291036 | GEO | 2025/03/05

REPOSITORIES: GEO

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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.

2025-03-05 | GSE291035 | GEO

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 [ChIP-Seq]

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

| PRJNA1231433 | ENA

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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Anoikis resistance drives transcriptional plasticity in pancreatic cancer

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

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A dominant-negative effect drives selection of <i>TP53</i> missense mutations in myeloid malignancies.

Project description:TP53, which encodes the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic human leukemia cell lines of the most common TP53 missense mutations. Functional, DNA-binding, and transcriptional analyses revealed loss of function but no GOF effects. Comprehensive mutational scanning of p53 single-amino acid variants demonstrated that missense variants in the DNA-binding domain exert a dominant-negative effect (DNE). In mice, the DNE of p53 missense variants confers a selective advantage to hematopoietic cells on DNA damage. Analysis of clinical outcomes in patients with acute myeloid leukemia showed no evidence of GOF for TP53 missense mutations. Thus, a DNE is the primary unit of selection for TP53 missense mutations in myeloid malignancies.

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Anoikis resistance drives transcriptional plasticity in pancreatic cancer

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Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer.

Project description:Pancreatic ductal adenocarcinoma (PDA) is characterized by an activating mutation in KRAS. Direct inhibition of KRAS through pharmacological means remains a challenge; however, targeting key KRAS effectors has therapeutic potential. We investigated the contribution of TANK-binding kinase 1 (TBK1), a critical downstream effector of mutant active KRAS, to PDA progression. We report that TBK1 supports the growth and metastasis of KRAS-mutant PDA by driving an epithelial plasticity program in tumor cells that enhances invasive and metastatic capacity. Further, we identify that the receptor tyrosine kinase Axl induces TBK1 activity in a Ras-RalB-dependent manner. These findings demonstrate that TBK1 is central to an Axl-driven epithelial-mesenchymal transition in KRAS-mutant PDA and suggest that interruption of the Axl-TBK1 signaling cascade above or below KRAS has potential therapeutic efficacy in this recalcitrant disease.

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Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer.

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