A novel mechanism by which PPDPF regulates pancreatic ductal adenocarcinoma

On December 1, 2022, the international academic journal Advanced Science published online the title "PPDPF promotes the development of mutant KRAS-driven pancreatic ductal adenocarcinoma by regulating the GEF activity of" by Xie Dong Research Group, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences SOS1"
.
This study reveals the important role of PPDPF in the development and progression of pancreatic ductal adenocarcinoma and provides a promising therapeutic strategy
for patients with PDAC with KRAS mutations.

Pancreatic cancer is one of the most malignant tumors in the world, and pancreatic ductal adenocarcinoma (PDAC) accounts for more than
95% of pancreatic cancers.
The 5-year overall survival rate for patients with PDAC is less than 5%.

Although surgery is the only treatment that effectively prolongs the survival time of patients with PDAC, the 5-year survival rate for patients undergoing surgical tumor resection is still less than 25%.

Although there has been substantial improvement in understanding of the mechanisms of pancreatic cancer, treatments for pancreatic cancer are still very limited
.
Therefore, exploring the molecular mechanism of the occurrence and development of pancreatic ductal adenocarcinoma helps to provide potential molecular targets for the treatment of PDAC
.

The RAS gene is the most commonly mutated oncogene
in human cancers.
KRAS mutations occur in 98% of PDAC patients, of which G12 mutations account for 97%
of KRAS mutations.
SOS1 is an important guanine nucleotide exchange factor (GEF) for RAS that activates RAS
by converting RAS-bound GDP to GTP.
After EGF activates EGFR, SOS1 is recruited onto the cell membrane and catalyzes the RAS-bound GDP-GTP exchange
.
The CDC25 and REM domains are the core domains of SOS1 (collectively known as the Cat domain) and perform catalytic functions
.
The REM domain contains an activated isomeric site that binds to RAS-GTP
.
When this site binds to RAS-GTP, it can further activate the CDC25 domain responsible for catalysis, thereby promoting the GDP-GTP exchange
of RAS.
The GEF activity of SOS1 is regulated by different mechanisms, including membrane localization and self-inhibition of SOS1, and phosphorylation of the C-terminal domain of SOS1 by MAPK
.
Previous studies have shown that GEF can bind GTP
.
However, it is unclear
what GEF means for combining GTP and whether SOS1 can bind GTP.

Pancreatic progenitor cell differentiation and proliferation factor (PPDPF) was first reported
in zebrafish.
PPDPF is an exocrine cytogenius with potential PDZ, SH2, SH3 and GTP binding sites
.
However, the biological function of PPDPF in pancreatic cancer is unclear
.

This study found that the expression of PPDPF in pancreatic cancer was significantly increased, and patients with high PPDPF expression had a poor
prognosis.
Knockout of PPDPF in a mouse model of pancreatic ductal adenocarcinoma significantly inhibits the occurrence and development
of Kras mutation-driven PDAC.
In addition, the researchers demonstrated that PPDPF can bind to GTP and provide GTP to SOS1, thereby enhancing its GEF activity and promoting the activation of KRAS
.
This study revealed the new function of PPDPF in PDAC and the new mechanism of KRAS activation regulation, providing a potential therapeutic target for PDAC
.

Dr.
Ni Qianzhi and doctoral student Zhu Bing of Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences are co-first authors of the paper, and associate researchers Li Jingjing and Xie Dong, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, are the corresponding authors
of this paper.
The research was supported by the National Natural Science Foundation of China and the Chinese Academy of Sciences, as well as the public technology platform and animal platform of the Shanghai Institute of Nutrition and Health
, Chinese Academy of Sciences.

Fig.
Schematic diagram of the mechanism of PPDPF regulating KRAS activation

Original link: https://doi.
org/10.
1002/advs.
202202448