Sustained IP3-linked Ca2+ signaling promotes progression of triple negative breast cancer cells by regulating fatty acid metabolism

Riccardo Filadi; Agnese De Mario; Matteo Audano; Patrizia Romani; Silvia Pedretti; Cesar Cardenas; Sirio Dupont; Cristina Mammucari; Nico Mitro; Paola Pizzo

doi:10.3389/fcell.2023.1071037

Sustained IP3-linked Ca²⁺ signaling promotes progression of triple negative breast cancer cells by regulating fatty acid metabolism

Front Cell Dev Biol. 2023 Mar 13:11:1071037. doi: 10.3389/fcell.2023.1071037. eCollection 2023.

Authors

Riccardo Filadi^{1

2}, Agnese De Mario², Matteo Audano³, Patrizia Romani⁴, Silvia Pedretti³, Cesar Cardenas^{5

6

7

8}, Sirio Dupont⁴, Cristina Mammucari^{2

9}, Nico Mitro^{3

10}, Paola Pizzo^{1

2}

Affiliations

¹ Neuroscience Institute, National Research Council (CNR), Padua, Italy.
² Department of Biomedical Sciences, University of Padova, Padua, Italy.
³ Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
⁴ Department of Molecular Medicine (DMM), University of Padova, Padua, Italy.
⁵ Faculty of Sciences, Universidad Mayor, Center for Integrative Biology, Santiago, Chile.
⁶ Geroscience Center for Brain Health and Metabolism, Santiago, Chile.
⁷ Buck Institute for Research on Aging, Novato, CA, United States.
⁸ Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, United States.
⁹ Myology Center (CIR-Myo), University of Padova, Padua, Italy.
¹⁰ Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy.

Abstract

Rewiring of mitochondrial metabolism has been described in different cancers as a key step for their progression. Calcium (Ca²⁺) signaling regulates mitochondrial function and is known to be altered in several malignancies, including triple negative breast cancer (TNBC). However, whether and how the alterations in Ca²⁺ signaling contribute to metabolic changes in TNBC has not been elucidated. Here, we found that TNBC cells display frequent, spontaneous inositol 1,4,5-trisphosphate (IP3)-dependent Ca²⁺ oscillations, which are sensed by mitochondria. By combining genetic, pharmacologic and metabolomics approaches, we associated this pathway with the regulation of fatty acid (FA) metabolism. Moreover, we demonstrated that these signaling routes promote TNBC cell migration in vitro, suggesting they might be explored to identify potential therapeutic targets.

Keywords: Ca2+; IP3; MCU; TNBC; acylcarnitine; breast cancer; fatty acids; mitochondria.

Grants and funding

This work was supported by grants from the Italian Ministry of University and Scientific Research (PRIN2017XA5J5N) and the University of Padova (SID2019) to PP; the National Research Council (Premio Scientifico 2018 DSB-CNR) to RF; the Veronesi Foundation Postdoctoral Fellowships 2020, 2021, 2022 and an AIRC MFAG 27453 to PR; the Worldwide Cancer Research grant 21-0156 and an AIRC Foundation investigator grant 21392 to SD; the ANID/FONDECYT 1200255 and ANID/FONDAP 15150012 grants to CC; SP is supported by Fondazione Umberto Veronesi. This work was also partially supported by the Ministry of University and Research (MUR) Progetto Eccellenza (2018–2022) to the Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano (MA, SP and NM) and partially by the Italian Ministry of Health with Ricerca Corrente and 5 × 1000 funds to NM. The authors thank also the University of Padova UNIPD Funds for Research Equipment (2015), as well as the CARIPARO Foundation (Fondazione Cassa di Risparmio di Padova e Rovigo) Excellence project 2017 (2018/113) and the Euro Bioimaging Project Roadmap/ESFRI from European Commission to T. Pozzan.