Decoding Pancreatic Tumorigenesis: Molecular Origins, Microenvironmental Complexity, and the Future of Early Detection

Abstract

Pancreatic cancer remains one of the most lethal malignancies worldwide, mainly because diagnosis commonly occurs at advanced stages, tumour biology is aggressive, and responses to conventional therapies are limited. Pancreatic ductal adenocarcinoma (PDAC), which represents approximately 90% of pancreatic cancers, is characterised by complex genomic alterations, metabolic reprogramming, dense stromal architecture, and an immunosuppressive tumour microenvironment. Current evidence supports a multistep model of pancreatic tumorigenesis in which driver mutations, tumour suppressor gene inactivation,       precursor lesions, and environmental and metabolic risk factors interact during disease initiation and progression. However, the earliest molecular events that initiate malignant transformation, and the mechanisms determining whether precursor lesions progress to invasive cancer, remain incompletely understood. This review synthesises current knowledge on the molecular and genetic basis of pancreatic cancer, hereditary predisposition, precursor lesions, environmental and metabolic risk factors, tumour microenvironmental interactions, and emerging diagnostic and therapeutic approaches. Particular attention is given to pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms as precursor lesions, the contribution of KRAS, TP53, CDKN2A, and SMAD4 alterations, and the role of stromal and immune components in disease progression and treatment resistance. Recent technologies, including liquid biopsy, circulating tumour DNA analysis, artificial intelligence-assisted imaging, and multi-omics approaches, may support earlier detection and improved risk stratification. Nevertheless, no single diagnostic modality currently provides sufficient accuracy for routine early detection. Addressing unresolved questions related to tumour initiation, lesion progression, immune evasion, and therapeutic resistance will be essential for improving screening strategies, identifying high-risk individuals, and developing more effective targeted interventions for patients with pancreatic cancer.