Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth.

Simone Vodret, Giannino Del Sal, Nico Mitro, Silvio Bicciato, Claudio Tripodo, Giovanni Blandino, Gustavo Baldassarre, Barbara Belletti, Fiamma Mantovani, Alessandra Rustighi, Silvano Piazza, Camilla Tombari, Ilenia Segatto, Sara Donzelli, Manuel Caputo, Davide Vacca, Valeria Cancila, Luca Triboli, Matteo Audano, Silvia Pedretti, Rebecca Bertolio, Alessandro Zannini

Journal: Nature communications 2023;14(1):6777

PMID: 37880212

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Abstract

Reprogramming of amino acid metabolism, sustained by oncogenic signaling, is crucial for cancer cell survival under nutrient limitation. Here we discovered that missense mutant p53 oncoproteins stimulate de novo serine/glycine synthesis and essential amino acids intake, promoting breast cancer growth. Mechanistically, mutant p53, unlike the wild-type counterpart, induces the expression of serine-synthesis-pathway enzymes and L-type amino acid transporter 1 (LAT1)/CD98 heavy chain heterodimer. This effect is exacerbated by amino acid shortage, representing a mutant p53-dependent metabolic adaptive response. When cells suffer amino acids scarcity, mutant p53 protein is stabilized and induces metabolic alterations and an amino acid transcriptional program that sustain cancer cell proliferation. In patient-derived tumor organoids, pharmacological targeting of either serine-synthesis-pathway and LAT1-mediated transport synergizes with amino acid shortage in blunting mutant p53-dependent growth. These findings reveal vulnerabilities potentially exploitable for tackling breast tumors bearing missense TP53 mutations.

Address: Department of Life Sciences, University of Trieste, 34127, Trieste, Italy.; International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park-Padriciano, 34149, Trieste, Italy.; DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, University of Milan, Milan, Italy.; Tumor Immunology Unit, Department of Health Science, Human Pathology Section, School of Medicine, University of Palermo, 90133, Palermo, Italy.; Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.; Unit of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, National Cancer Institute, 33081, Aviano, Italy.; IFOM ETS, the AIRC Institute of Molecular Oncology, Milan, Italy.; Center for Genome Research, University of Modena and Reggio Emilia, 41125, Modena, Italy.; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.; Department of Life Sciences, University of Trieste, 34127, Trieste, Italy. [email protected].; International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park-Padriciano, 34149, Trieste, Italy. [email protected].; IFOM ETS, the AIRC Institute of Molecular Oncology, Milan, Italy. [email protected].

DOI: 10.1038/s41467-023-42458-1

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MeSH Terms: Female, Humans, Amino Acids, Amino Acids, Essential, Breast Neoplasms, Glycine, Large Neutral Amino Acid-Transporter 1, Serine, Tumor Suppressor Protein p53