PRIN 2022 - COD. 20227YTZE3 -"Deciphering tumor microenvironmental Acidosis and calcium channels...." - Finanziamento dell’Unione Europea – NextGenerationEU – missione 4, componente 2, investimento 1.1.

The prognosis of pancreatic ductal adenocarcinoma is extremely poor with 5 year survival rates of only about 8% for European PDAC patients. The poor prognosis results from therapeutic failure due to its aggressive metastatic behavior and late diagnosis. Indeed current therapies such as gemcitabine monotherapy (considered the standard therapy since 1997) or in combination with other drugs (gemcitabine/nap-paclitaxel or oxaliplatin (FOLFIRINOX)), have little impact on prognosis due compensatory escape mechanisms. The development of combination inhibitor strategies to overcome drug resistance is therefore a urgent need. One of the most prominent factors determining its very poor outcome is the extremely hypovascularized tumor microenvironment (TME) characterized by low pH, hypoxia and abundant extracellular matrix (ECM) proteins (desmoplasia). In particular, the acidic TME drives PDAC progression by selecting for more aggressive cell phenotypes although the underlying mechanism is still not clear. In this context, Ca2+ channels represent good target candidates due to their ability to integrate signals from the TME. Ca2+ channels are indeed pH and hypoxia sensors and alterations in Ca2+ homeostasis and expression in cancer progression and vascularization have been extensively reported. However the functional role of the TME in cancer progression is still poorly studied. Besides being functionally interconnected with each other, ion channels are physically and functionally linked to growth factor receptors among which fibroblast growth factor receptor 2 (FGFR2) is particularly involved in PDAC metastatic behavior as well as in Ministero dell'Università e della Ricerca MUR - BANDO 2022 TME acidosis. AdaPtiviTy relies on the new hypothesis that PDAC initiation and progression are due to the close interplay between tumor driver mutations and pancreatic acid-base dynamics that impact on pH-dependent Ca2+ channel network and FGFR axis in cancer cells and cancer stem cells. Based on the literature and our previous data, we hypothesize that the cross talk between acidic microenvironment and cancer cells modulate in turn the PDAC vasculature ( ). The main objective of the AdaPtiviTy project is to decipher the crosstalk between TME acidosis and Ca2+ channel/FGFR2 axis network 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.