p53-driven lipidome influences non-cell-autonomous lysophospholipids in pancreatic cancer

Springer Science and Business Media LLC - Tập 17 Số 1 - 2022
Alessio Butera1, Micaela Kalani Roy2, Carlotta Zampieri1, Eleonora Mammarella1, Emanuele Panatta1, Gerry Melino1, Angelo D’Alessandro2, Ivano Amelio3
1Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
2University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
3School of Life Sciences, University of Nottingham, Nottingham, UK

Tóm tắt

AbstractAdaptation of the lipid metabolism participates  in cancer pathogenesis, facilitating energy storage and influencing cell fate and control of molecular signalling. The tumour suppressor protein p53 is a molecular hub of cell metabolism, supporting antioxidant capabilities and counteracting oncogene-induced metabolic switch. Despite extensive work has described the p53-dependent metabolic pathways, a global profiling of p53 lipidome is still missing. By high-throughput untargeted lipidomic analysis of pancreatic ductal adenocarcinoma (PDAC) cells, we profile the p53-dependent lipidome, revealing intracellular and secreted lysophospholipids as one of the most affected class. Lysophospholipids are hydrolysed forms of phospholipids that results from phospholipase activity, which can function as signalling molecules, exerting non-cell-autonomous effects and instructing cancer microenvironment and immunity. Here, we reveal that p53 depletion reduces abundance of intracellular lysophosphatidyl-choline, -ethanolamine and -serine and their secretion in the extracellular environment. By integrating this with genomic and transcriptomic studies from in vitro models and human PDAC patients, we identified potential clinically relevant candidate p53-dependent phospholipases. In particular PLD3, PLCB4 and PLCD4 expression is regulated by p53 and chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) indicates a direct transcriptional control on their chromatin accessible genomic loci. Consistently, PLD3, PLCB4 and PLCD4 expression correlates with p53 mutational status in PDAC patients, and these genes display prognostic significance. Overall, our data provide insights into lipidome rewiring driven by p53 loss and identify alterations of lysophospholipids as a potential molecular mechanism for p53-mediated non-cell-autonomous molecular signalling that instructs cancer microenvironment and immunity during PDAC pathogenesis.

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