The molecular biology of pancreatic adenocarcinoma

Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence. Furthermore, it is usually diagnosed at an advanced stage with a very dismal prognosis. Due to the high heterogeneity, metabolic reprogramming, and dense stromal environment associated with pancreatic cancer, patients benefit little from current conventional therapy. Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification, thus expanding clinical therapeutic options. In this review, we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression.

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Fig: The characteristics of pancreatic adenocarcinoma. Pancreatic cancer is a common cause of cancer mortality characterized by high heterogeneity, a dense stromal tumor microenvironment (TME), highly metastatic propensity, metabolic reprogramming, and limited benefits from current conventional therapies. aGenetic and epigenetic changes in pancreatic cancer. KRAS (~90%), TP53 (50–74%), CDKN2A (46–60%), and SMAD4 (31–38%) are the most frequently mutated genes known to modulate the initiation and progression of pancreatic cancer. Epigenetic regulatory genes, including MLL2/3, KDM6A, and multipleHDACs encoding genes, regulate histone modification. SMARCA2/4 and ARID2modulate chromatin remodeling. b Therapeutic limitations in pancreatic cancer. Surgical resection is the only potentially curative choice for pancreatic cancer patients. Adjuvant chemotherapy can only partially improve the overall survival of pancreatic cancer patients c Pancreatic cancer is an extremely aggressive tumor with high metastatic propensity. The immunosuppressive TME plays an important role in modulating the metastasis of pancreatic cancer cells to the liver, lungs, peritoneum, and bone. d Metabolic reprogramming of pancreatic cancer. Pancreatic cancer cells can survive and proliferate in stressful microenvironments by reprogramming energy metabolism to increase glucose and glutamine uptake, macropinocytosis, and autophagy

We further discuss potential biomarkers for pancreatic cancer diagnosis, prediction, and surveillance based on novel liquid biopsies. We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models. Finally, we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.

Wang, S., Zheng, Y., Yang, F. et al. The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives.Sig Transduct Target Ther 6, 249 (2021). https://doi.org/10.1038/s41392-021-00659-4

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