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

Camilla Tombari, Alessandro Zannini, Rebecca Bertolio, Silvia Pedretti, Matteo Audano, Luca Triboli, Valeria Cancila, Davide Vacca, Manuel Caputo, Sara Donzelli, Ilenia Segatto, Simone Vodret, Silvano Piazza, Alessandra Rustighi, Fiamma Mantovani, Barbara Belletti, Gustavo Baldassarre, Giovanni Blandino, Claudio Tripodo, Silvio Bicciato, Nico Mitro and Giannino Del Sal ()
Additional contact information
Camilla Tombari: University of Trieste
Alessandro Zannini: University of Trieste
Rebecca Bertolio: University of Trieste
Silvia Pedretti: University of Milan
Matteo Audano: University of Milan
Luca Triboli: University of Trieste
Valeria Cancila: University of Palermo
Davide Vacca: University of Palermo
Manuel Caputo: University of Trieste
Sara Donzelli: IRCCS Regina Elena National Cancer Institute
Ilenia Segatto: Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, National Cancer Institute
Simone Vodret: Area Science Park-Padriciano
Silvano Piazza: Area Science Park-Padriciano
Alessandra Rustighi: University of Trieste
Fiamma Mantovani: University of Trieste
Barbara Belletti: Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, National Cancer Institute
Gustavo Baldassarre: Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, National Cancer Institute
Giovanni Blandino: IRCCS Regina Elena National Cancer Institute
Claudio Tripodo: University of Palermo
Silvio Bicciato: University of Modena and Reggio Emilia
Nico Mitro: University of Milan
Giannino Del Sal: University of Trieste

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42458-1

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