Ricerc@Sapienza

Type 1 and type 2 diabetes confer an excess pancreatic cancer (PaC) risk of similar magnitude, suggesting a common mechanism. We have shown that Advanced glycation end-products (AGEs), the levels of which are increased in both types of diabetes, promote PaC growth and that the L-carnosine derivative FL-926-16 is highly effective in preventing the PaC-promoting effect of diabetes by counteracting carbonyl stress. This project is aimed at i) demonstrating that glucose-related reactive carbonyl species (RCS) and their protein adducts (i.e., AGEs) induce the activation of YAP, a downstream target of KRAS signalling, and ii) validating a molecular mechanism implicating carbonyl stress-mediated YAP induction through decrease of the tumor suppressor LATS1, a negative regulator of YAP, and increase of EGFR phosphorylation, a known YAP activating factor. These objectives will be pursued by investigating:
1. the role of RCS and AGEs (i.e., carbonyl stress) as mediators of the proliferation-promoting effect of high glucose (HG) through activation of a LATS1/EGFR/YAP pathway in human pancreatic ductal adenocarcinoma (PDA) cells;
2. the protective effects of the RCS-sequestering and AGE inhibitor compound FL-926-16 on glucose-, RCS- and AGE-induced proliferation and YAP activition in PDA cells;
3. the effects of diabetes and FL-926-16 on the levels of AGEs and YAP activity in PaC specimens from the Pdx1-Cre;LSL-KrasG12D/+ (KC) mouse model;
4. the association between AGEs and nuclear YAP levels in human pancreatic adenocarcinoma tissues;
5. the effects of serum from diabetic patients on proliferation and activation of a LATS1/EGFR/YAP axis in PDA cells.
Overall, this study will clarify the mechanisms underlying the diabetes-cancer link and will provide evidence that carnosine derivatives represent a promising class of RCS-scavenging agents useful not only in metabolic disorders, but also in risk management and prevention of cancer, particularly in high-risk diabetic patients.