Titolo: The impact of mechanics on nuclear integrity, mitochondria metabolisms and inflammatory responses in carcinoma

Responsabile scientifico per il DMM: Prof. Sirio Dupont

Codice Progetto: 2022T9RM8A
Coordinatore: Università degli Studi di MILANO - Prof. Giorgio SCITA

Partner-Unità di ricerca: Università degli Studi di FIRENZE - Università degli Studi di PADOVA

Bando: PRIN 2022 - Decreto Direttoriale n. 104 del 02-02-2022
Durata: 28/09/2023 - 27/09/2025 (24 mesi)

Finanziamento progetto: € 259.390,00 - CUP C53D23003190006

 

Abstract del progetto

The mechanical properties of cells and tissues are emerging as pivotal regulators of cell behavior and fate in physiology and pathology, including during breast carcinoma (BCC) progression and dissemination. Here, we propose to characterize the nanoscopic (at the level of cell adhesion molecules), microscopic (cellular), and mesoscopic (tissue level) mechano-adaptation of BCC cells when they invade tissues to metastasize. We recently found that tissue fluidification (i.e., the transition from a solid-to-fluid state characterized by altered cell-cell adhesions and collective migration, also called jamming-to-unjamming transition) corresponds to a biphasic behavior of alpha-catenin, the main cell-cell adhesion junctional protein, which can switch from a force-induced and -bearing solid state to a “slipping” fluid one. We also found that when BCCs leave the primary tumor, which is actively promoted by fluidification, and invade soft distal tissues, activate two signaling mechanisms that conspire to promote the cGAS/STING pathway, which detects cytosolic DNA to trigger an inflammatory state. Surprisingly, both fluidification and the response to a soft ECM entail changes in mitochondrial dynamics, with the cytoplasmic release of mitochondrial DNA and its oxidation in response to mitochondrial ROS, which are among the most powerful inducers of cGAS/STING. This supports the hypothesis that collective dynamics through tissue fluidification, and adaptation to ECM mechanics exerts physical forces and mechanical stress that shape mitochondrial functions including metabolic, inflammatory, and oxidative responses. We posit that these changes ultimately influence the acquisition of metastatic traits and the ability of BCCs to evade chemotherapy.

Our group blends a multidisciplinary team of investigators with recognized expertise tailored to unravel the biomechanical adaptive response of BCCs at multiscale levels, focusing on (i) how junctional and cytoskeletal interactions respond to mechanical forces through biophysical and single-molecule approaches (Capitanio), (ii) how junctional forces regulate fluidification and collective motility by combining biophysical modeling and multicellular system in 2D and 3D (Scita), (iii) how junctional forces regulate nuclear integrity, mitochondrial dynamics and associated signaling and metabolic events (Scita, Dupont), and (iv) how these forces cross-talks with elastic forces across cell-ECM adhesions to regulate downstream events and therapy resistance (Dupont).

This project will provide an integrated view of how cells respond to their mechanical microenvironment, an emergent topic in cell and tissue biology. As this general concept will be developed in the context of BCCs, the project has also the potential to break new ground toward future scenarios in which cancer mechanical vulnerabilities are first rationally tested in vitro and then used to inform treatment.