p53 alterations modulate cellular fate determinations in the development of Pancreatic Ductal Adenocarcinoma

Pancreatic cancer is a highly lethal malignancy with a very low 5-year survival rate. The most common type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). During the development of PDAC, cancer cells undergo extensive metabolic rewiring to support their growth and adapt to the tumor microenvironment. This metabolic reprogramming involves alterations in glucose, amino acid, and lipid pathways. Mutant KRAS and MYC, both commonly found in PDAC, are known to trigger metabolic rewiring, including changes in lipid metabolism. Understanding the mechanisms underlying the development of this highly aggressive form of cancer is crucial. Research efforts have delved into investigating gene alterations and identifying key genes implicated in driving its aggressiveness. Notably, one of the prominent gatekeepers identified in this context is the tumor suppressor gene known as p53. Traditionally hailed as the guardian of the genome, p53 plays a multifaceted role in cellular processes. Its responsibilities encompass cell cycle arrest, DNA damage repair, promotion of cellular senescence, and regulation of metabolism. The tightly regulated functions of p53 are paramount in preserving genomic stability and curbing the emergence of cancer. Consequently, disruption of p53 functionality results in the loss of these critical functions, ultimately fostering the development of cancer cells. In PDAC, p53 alterations have been observed in more than 70% of cases, underscoring its significance in the disease. Our research project aimed to analyze the consequences of these p53 alterations, seeking to elucidate their role in the progression of this aggressive form of pancreatic cancer. Central to our investigation were inquiries into the gene and epigenetic alterations associated with p53 loss of function. Additionally, we explored the impact of p53 alterations on metabolic regulation and the initiation of pro-tumor signaling pathways. Furthermore, our analysis encompassed missense mutations that not only contribute to the loss of p53 function but also endow it with oncogenic properties, transforming it into a potent driver of cancer. Through unraveling the intricate interplay between p53 and these interconnected factors, our study unveils new possibilities for therapeutic interventions that could substantially enhance patient outcomes. Moreover, this research lays the groundwork for further exploration of these pathways, potentially paving the way for the development of targeted treatments that effectively combat PDAC.