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p53 mutations define the chromatin landscape to confer drug tolerance in pancreatic cancer

p53 mutations define the chromatin landscape to confer drug tolerance in pancreatic cancer

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ZAMPIERI, Carlotta, Emanuele PANATTA, Vincenzo CORBO, Alessandro MAURIELLO, Gerry MELINO, Ivano AMELIO, 2022. p53 mutations define the chromatin landscape to confer drug tolerance in pancreatic cancer. In: Molecular Oncology. Wiley. 16(6), pp. 1259-1271. ISSN 1574-7891. eISSN 1878-0261. Available under: doi: 10.1002/1878-0261.13161

@article{Zampieri2022-03mutat-56462, title={p53 mutations define the chromatin landscape to confer drug tolerance in pancreatic cancer}, year={2022}, doi={10.1002/1878-0261.13161}, number={6}, volume={16}, issn={1574-7891}, journal={Molecular Oncology}, pages={1259--1271}, author={Zampieri, Carlotta and Panatta, Emanuele and Corbo, Vincenzo and Mauriello, Alessandro and Melino, Gerry and Amelio, Ivano} }

Amelio, Ivano Mauriello, Alessandro Corbo, Vincenzo Panatta, Emanuele p53 mutations define the chromatin landscape to confer drug tolerance in pancreatic cancer Melino, Gerry 2022-02-09T10:38:43Z 2022-02-09T10:38:43Z Mauriello, Alessandro Zampieri, Carlotta Attribution 4.0 International eng 2022-03 Melino, Gerry Amelio, Ivano Somatic inactivation of p53 (TP53) mainly occurs as missense mutations that lead to acquisition of neomorphic mutant protein forms. p53 mutants have been postulated to exert gain-of-function (GOF) effects, including promotion of metastasis and drug tolerance, which generally contribute to acquisition of the lethal phenotype. Here, by integrating a p53<sup>R270H</sup> -dependent transcriptomic analysis with chromatin accessibility (ATAC-seq) profiling, we shed light on the molecular basis of a p53 mutant-dependent drug-tolerant phenotype in pancreatic cancer. p53<sup>R270H</sup> finely tunes chromatin accessibility in specific genomic loci, orchestrating a transcriptional programme that participates to phenotypic evolution of the cancer. We specifically focused on the p53<sup>R270H</sup> -dependent regulation of the tyrosine kinase receptor macrophage-stimulating protein receptor (MST1r). MST1r deregulation substantially impinged on drug response in the experimental model, recapitulating the p53<sup>R270H</sup> -dependent phenotype, and strongly correlated with p53 mutant and aggressive phenotype in pancreatic cancer patients. As cellular plasticity in the final stages of evolution of pancreatic cancer seems to predominantly originate from epigenetic mechanisms, we propose that mutant p53 participates in acquisition of a lethal phenotype by fine-tuning the chromatin landscape. Panatta, Emanuele Zampieri, Carlotta Corbo, Vincenzo

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