Mechanistic integration of genetic alterations, PTM signaling, and tumor microenvironment remodeling in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, with late diagnosis, rapid progression, considerable therapy resistance, and low overall survival. Growing evidence suggests that PDAC progression is not determined by simple genetic events but rather depends on a multitude of genetic susceptibilities, post-translational modifications (PTMs), metabolic dysregulation, chronic inflammation, and dynamic remodeling of the tumor microenvironment (TME). Germline and somatic alterations, including KRAS, TP53, BRCA1/2, ATM, and SMAD4, impact genomic instability and oncogenic signaling, whereas inflammatory and metabolic pathologies like chronic pancreatitis, obesity, and type 2 diabetes mellitus promote acinar-to-ductal metaplasia (ADM) and tumor initiation. PTMs such as phosphorylation, ubiquitination, acetylation, methylation, and glycosylation are among the key regulators of signaling pathways including MAPK, PI3K/AKT, NF-κB, and STAT3, affecting the plasticity of cellular organization, epithelial–mesenchymal transition (EMT), immune evasion, and therapeutic resistance. In parallel, the desmoplastic TME, composed of cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), immune suppressor cells, and hypoxic metabolic conditions, potentiates tumor advancement through co-signaling cascades with tumor cells. The objective of this review is to provide a comprehensive, systems-based analysis of PDAC by correlating the changes at the genomic level, PTM-mediated signaling, and microenvironmental factors, along with mapping how genomic, PTM, and microenvironmental changes interact to drive cancer, progression, and treatment resistance. In addition, the importance of multi-omics analysis, which includes genomics, proteomics, and metabolomics, for biomarker identification and precision medicine is emphasized. Whereas existing research have tended to study either genetics, PTMs, or TMEs separately, this review instead traces the mechanistic thread that connects them into a single integrated framework. This allows the researcher not only to develop a deeper understanding of the biology of diseases but also to discover new opportunities for therapy as well.