Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth
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 can...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42458-1 |
| _version_ | 1827710005507260416 |
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| author | 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 Giannino Del Sal |
| author_facet | 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 Giannino Del Sal |
| author_sort | Camilla Tombari |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:31:08Z |
| format | Article |
| id | doaj.art-ed8691094df743f6a79d37fb5d803a8a |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:31:08Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-ed8691094df743f6a79d37fb5d803a8a2023-11-20T10:01:18ZengNature PortfolioNature Communications2041-17232023-10-0114112110.1038/s41467-023-42458-1Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growthCamilla Tombari0Alessandro Zannini1Rebecca Bertolio2Silvia Pedretti3Matteo Audano4Luca Triboli5Valeria Cancila6Davide Vacca7Manuel Caputo8Sara Donzelli9Ilenia Segatto10Simone Vodret11Silvano Piazza12Alessandra Rustighi13Fiamma Mantovani14Barbara Belletti15Gustavo Baldassarre16Giovanni Blandino17Claudio Tripodo18Silvio Bicciato19Nico Mitro20Giannino Del Sal21Department of Life Sciences, University of TriesteDepartment of Life Sciences, University of TriesteDepartment of Life Sciences, University of TriesteDiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, University of MilanDiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, University of MilanDepartment of Life Sciences, University of TriesteTumor Immunology Unit, Department of Health Science, Human Pathology Section, School of Medicine, University of PalermoTumor Immunology Unit, Department of Health Science, Human Pathology Section, School of Medicine, University of PalermoDepartment of Life Sciences, University of TriesteTranslational Oncology Research Unit, IRCCS Regina Elena National Cancer InstituteUnit of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, National Cancer InstituteInternational Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park-PadricianoInternational Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park-PadricianoDepartment of Life Sciences, University of TriesteDepartment of Life Sciences, University of TriesteUnit of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, National Cancer InstituteUnit of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, National Cancer InstituteTranslational Oncology Research Unit, IRCCS Regina Elena National Cancer InstituteTumor Immunology Unit, Department of Health Science, Human Pathology Section, School of Medicine, University of PalermoCenter for Genome Research, University of Modena and Reggio EmiliaDiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, University of MilanDepartment of Life Sciences, University of TriesteAbstract 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.https://doi.org/10.1038/s41467-023-42458-1 |
| spellingShingle | 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 Giannino Del Sal Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth Nature Communications |
| title | Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth |
| title_full | Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth |
| title_fullStr | Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth |
| title_full_unstemmed | Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth |
| title_short | Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth |
| title_sort | mutant p53 sustains serine glycine synthesis and essential amino acids intake promoting breast cancer growth |
| url | https://doi.org/10.1038/s41467-023-42458-1 |
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