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Fiorio Pla -Deciphering Tumor microenvironmental triggers and Ca2+ channels crosstalk in PDAC progression- bando Grant for Internationalization- GFI" 2022

Progetto
The prognosis of pancreatic ductal adenocarcinoma (PDAC) is extremely poor with 5-year survival rates of only 8% for European PDAC patients. The poor prognosis results from therapeutic failure due to its aggressive metastatic behavior and late diagnosis. Despite intensive research, PDAC is still one of the most aggressive and intractable cancers. Unconventional approaches are clearly needed to tackle the disease. New experimental therapeutical approaches remain therefore urgent for the treatment and/diagnosis of PDAC. One of the most prominent factors determining its very poor outcome is the extremely hypovascularized tumor microenvironment (TME) characterized by special physical-chemical properties including abundant amounts of extracellular matrix (ECM) proteins within the tumor (desmoplasia) and a highly acidic and hypoxic microenvironment. The excessive production of a stiff ECM has a major impact on the mechanical properties of PDAC which in turn feeds back onto the tumor (stroma) cells. Indeed PDAC, it is characterized by an extremely elevated ECM deposition that causes increased pressure which can be also 10 fold higher than normal pancreatic pressure (8 mmHg, ~1,066 KPa), reaching the value of nearly 100 mmHg (~13,33 KPa). This stiffness leads in turn to a massive increase in interstitial fluid pressure (IFP). This pressure impairs vascular function leading to intratumoral vessel collapse and tumor permeability and therefore difficult chemotherapy and immunotherapy treatments PDAC is indeed an hypovascularized tumor in later stages with the microvessel density (MVD) inversely associated with stromal area, and when decreased, associated with poor survival. However, at early stages nearby vessels are important means for cancer cells spreading. Interestingly, a recent report demonstrated that PDAC cells promote vessel ablation in a 3D vessel on chip model as well as in vivo, suggesting that the reduction in vascularization is not due to a reduction of angiogenesis but to ablation of endothelial cells by invading cancer cells. Understanding the interplay between TME, cancer cells and vascular endothelium will give important information about PDAC progression. In this context, Ca2+ channels represent ideal target candidates due to their ability to integrate signals from the TME. Ca2+ channels are indeed mechano-sensors and alterations in Ca2+ homeostasis and Ca2+ channel expression in cancer progression and vascularization have been extensively reported by several groups including UNITO group. Emerging evidence indicates that this is particularly relevant in cancer, including PDAC. These results gave rise to consider cancer development and progression as a special form of "channelopathy". In particular, the discovery of the Transient Receptor Potential (TRP) superfamily of channels, Store-Operated channels (SOC) and PIEZO channels, provided putative candidates for non-voltage-gated Ca2+ entry mechanisms and represent potentially useful targets for the development of personalized innovative anti-cancer therapies. Most importantly, these channels are critical for the ability of cancer and stroma cells to respond to the physical-chemical cues from the PDAC TME. However, the functional role of the TME in cancer progression is still under study. The main objective of the present project is to decipher the crosstalk between TME mechanical stress and Ca2+ signalling in PDAC in order to (i) advance in the knowledge of stroma/tumor signaling mechanisms underlying PDAC progression and (ii) design more effective combination therapies overcoming chemoresistance. We will focus on the remodeling of Ca2+ channels activity and functional role induced by the local microenvironmental mechanical stimuli. Due to our preliminary results showing a role for SOC channels in PDAC cell migration, we will start testing the hypothesis that ORAI1 and STIM1, the main actors for SOC, are implicated in the mechanical stimulation of PDAC cell
  • Dati Generali
  • Aree Di Ricerca

Dati Generali

Partecipanti (4)

FIORIO PLA Alessandra   Responsabile scientifico  
GENOVA Tullio   Partecipante  
MUNARON Luca Maria   Partecipante  
RUFFINATTI Federico Alessandro   Partecipante  

Referenti

LO IACONO Cristiano   Amministrativo  

Dipartimenti coinvolti

SCIENZE DELLA VITA E BIOLOGIA DEI SISTEMI   Principale  

Tipo

Grant for Internationalization - GFI - Programmazione Triennale 21-23

Finanziatore

Ministero dell'Università e della Ricerca
Ente Finanziatore

Partner

Università degli Studi di TORINO

Contributo Totale (assegnato) Ateneo (EURO)

12.600€

Periodo di attività

Luglio 28, 2022 - Dicembre 22, 2023

Durata progetto

17 mesi

Aree Di Ricerca

Settori (12)


LS3_5 - Cell signalling and signal transduction - (2020)

Settore BIO/09 - Fisiologia

CIBO, AGRICOLTURA e ALLEVAMENTI - Allevamento e Produzioni Animali

CIBO, AGRICOLTURA e ALLEVAMENTI - Farmacologia Veterinaria

CIBO, AGRICOLTURA e ALLEVAMENTI - Patologia e malattie degli animali

MEDICINA, SALUTE e BENESSERE - Epidemiologia

MEDICINA, SALUTE e BENESSERE - Oncologia e Tumori

MEDICINA, SALUTE e BENESSERE - Ricerca Traslazionale e Clinica

MEDICINA, SALUTE e BENESSERE - Trapianti e medicina rigenerativa

SCIENZE DELLA VITA e FARMACOLOGIA - Farmacologia, Biochimica e Biologia Molecolare

SCIENZE DELLA VITA e FARMACOLOGIA - Fisiologia

SCIENZE DELLA VITA e FARMACOLOGIA - Interazioni tra molecole, cellule, organismi e ambiente
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