Project Funding Details

A curative treatment for pancreatic adenocarcinoma (PaAd) is only available to rare cases, mostly related to incidental imaging findings. We found that the heterotrimeric G-proteins Galphas and Galpha15 are involved in PaAd insurgency. Activating mutations of GNAS, Galphas encoding gene, and the ectopic expression of GNA15, Galpha15 encoding gene, occur in pre-neoplastic lesions and represents early drivers that unfortunately are extremely difficult to target pharmacologically. This project continues efforts by our lab supported by two previous AIRC grants. Our preliminary results point to a highly specific signature of genes associated with GNA15. They encode e transmembrane proteins that mediate dynamic extracellular interactions, cell signaling and proteolysis, all hallmarks of invasiveness. Most of these proteins have been implicated in cell transformation, and represent much better therapeutic targets than G proteins. We hypothesize that the combination of transmembrane proteins and proteases associated with GNA15 and mutant GNAS are part of molecular machinery specifically assembled in pre-neoplastic lesions and are instrumental to the early dissemination of the disease. Specific proteases and G protein coupled receptors activated by ligands like neuromedin and Wnt are integral components of these signaling complexes. 1) validate and refine the combination of targets part of the signature, including specific epitopes generated by the cleavage of the transmembrane proteins by the proteases 2) investigate the functional role of the signature in PaAd insurgency 3) exploit the signature to provide novel diagnostic tools or the basis to improve therapy. Utilizing immunofluorescence and in situ hybridization we will investigate human PaAd cells lines and tissues to validate and refine the composition of the GNA15 signature. Aim1 and aim2 will use microscopy, FRET, phosphoproteomic, RNAseq techniques and two mouse models is dedicated to understand the mechanism and the effects associated to the anomalous signaling mediated by Galphas and Galpha15. In order to translate these findings to therapy, we will trace the signature or specific newly formed epitopes in liquid biopsies. To this purpose we will analyze plasma for differentially methylated cell free DNA, extracellular vesicles simultaneously expressing signature members, proteolytic products and test novel PET protocols. We expect to establish a combination of targets highly specific for PaAd, particularly interesting because distinctive of the cellular component that disseminate the disease outside the pancreas during the asymptomatic phase and elude the resection of localized disease. The validation of the signature can translate to multiple novel therapeutic approaches, specifically: - liquid biopsies to diagnose PaAd and support the indication for surgical intervention and predict relapse, - immunoPET capable to detect early lesions and residual disease that evades surgery - novel targets for CarT based therapies and theranostic approaches