Mechanisms that modulate endoplasmic reticulum/mitochondria calcium signaling to improve cancer chemotherapy efficacy

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Abstract:

Calcium (Ca2+) signaling is a physiological process composed of a complex and interconnected series of events that play a key role in maintaining the health of the cell. Its dysregulation led to several pathologies, including cancer. Cells have particular microdomains where many of these signaling events take place, called mitochondria-associated membranes (MAMs), an area where the endoplasmic reticulum (ER) and mitochondria are in close contact and where the communication via the second messenger Ca2+ takes place. In this particular microenvironment there are mitochondrial proteins (i.e. MCU complex), reticular proteins (i.e. IP3Rs and SERCA) and regulators interacting with them (i.e. BAP1, PML and PTEN). The collaborations between all these actors led to the fine-tuning of Ca2+ ion flux, which is essential for the maintenance of physiological conditions. Specifically, it has been described how the perturbation of the amount or functionality of any of the cited proteins is involved in different tumor pathologies. The aim of this project is to unravel this delicate signaling pathway in three different tumoral contexts: colon and lung carcinomas, and malignant mesothelioma (MM). To address this point we will derive primary cell cultures from both healthy and cancer human tissues, then we will evaluate Ca2+ ion homeostasis in the ER, mitochondria and cytosol. These studies will be followed by the evaluation of the pool of proteins that play a key role in the Ca2+ ion signaling pathway and are correlated to the cancer staging of the tumor analyzed. About 4-17% of cancers are attributable to germline mutations, namely pathogenic gene variants occurring de novo in the germline or as part of a hereditary cancer syndrome. As result, the identification of inherited mutations that predispose to cancer provides significant benefit to the patient and for at-risk relatives. Scientific evidence, also coming from our research group, demonstrates how the presence of a protein is not sufficient to prove its functionality. For these reasons samples that showed perturbations on ER-mitochondria Ca2+ homeostasis that are not reflected in protein amount will be subjected to in-depth analysis of transcriptome-wide changes in RNA expression patterns of Ca2+ signaling key proteins coding genes. In the final phases, we will mimic in vitro the identified cancer patients’ mutations to evaluate if these are sufficient to recreate the perturbations of the Ca2+ signaling previously observed on primary cultures. Lastly, we will test different Ca2+ modulators to find new Ca2+-based potential therapies, wich will be beneficial in association with tumor-specific traditional treatments.

Dettagli progetto:

Referente scientifico: Pinton Paolo

Fonte di finanziamento: Bando PRIN 2022 PNRR

Data di avvio: 30/11/2023

Data di fine: 30/11/2025

Contributo MUR: 154.444 €

Partner:

  • Università degli Studi di FERRARA (capofila)
  • Università degli Studi "Magna Graecia" di CATANZARO