Role of tumor microenviroment in Pancreatic Ductal Adeno Carciroma development: identification of Potential therapeutic targets

PIANO NAZIONALE DI RIPRESA E RESILIENZA (PNRR)

Missione 4 - Componente 2 - Investimento 1.1

“Fondo per il Programma Nazionale della Ricerca (PNR) e Progetti di Ricerca di Rilevante Interesse Nazionale (PRIN)” - Finanziato dall’Unione europea – NextGenerationEU

Bando PRIN 2022

D.D. n. 104 del 02.02.2022

Progetto “Role of tumor microenvironment in Pancreatic Ductal Adeno Carcinoma development: identification of potential therapeutic targets”

Codice Identificativo Progetto: 2022Y7J83C- CUP: D53D23014580006

PDAC prognosis is very poor (1-2). A major role in PDAC development and unresponsiveness to therapies is played by the desmoplastic tumour microenvironment (TME). Excessive fibrosis, causing defective vascularity and hypoxia, results in selecting apoptosis- resistant tumour clones, while hindering immune cells recruitment to the tumour nest and drugs delivery. Importantly, paracrine tumour-TME cells circuits sustain tumour cell survival and growth and suppress the anti-tumour response (3). KRAS oncogenes are major drivers in PDAC. RAS is a GTP hydrolase that alternates between an inactive GDP-bound and an active GTP-bound state; activated RAS triggers various intracellular signaling pathways, mediated by MAPKs, PI3K and RalGEF-Ral, regulating cell survival, proliferation and other cellular processes. KRAS oncogenes are present in over 90% of PDACs; hot spot mutations that predominantely occur in codons 12 and 13 result in defective GTPase activity, locking the protein into an active GTP-bound state. However, oncogenic KRAS leads also to the neoplastic cell production of cytokines and chemokines that impact on TME cells, modulating their recruitment, survival, activation and/or polarization, and improving the TME pro-tumour activity. In this context, a pro-tumour activity is exerted by BAG3 protein (4). BAG3 is released (extracellular BAG3: eBAG3) by PDAC cells and binds to its receptor (eBAG3R) on tumour- associated macrophages (TAMs) and fibroblasts (CAFs), inducing the release of pro-tumour cytokines and chemokines and tissue fibrosis (4-7).
We have been studying PDAC biology and particularly the role of TME in cancer development for years, in this project we plan to further investigate the role of TME in PDAC development and particularly the pathways leading to TME remodeling in KRAS mutated PDACS. We will also focus our studies on the role of TME in resistance to treatment with KRAS inhibitors. Finally we will investigate the potential of combined treatment between KRAS inhibitors with therapies acting on the TME, starting with a combination with anti-BAG3 treatment that we already shown to affect PDAC growth. Most of the studies described below will be performed on in vivo models, that, although technically challenging, are the only models that allow to investigate the interaction between the cancer cells and its microenvironment. Studies include a thorough investigation of the cell populations present in the tumor TME as well as open proteomic, phosphor-proteomic and transcriptomic studies to identify the pathways involved in the cross talk between cancer cells and its environment.