The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives

Abstract

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. 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.

Fig. 1

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. a Genetic 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 multiple HDACs encoding genes, regulate histone modification. SMARCA2/4 and ARID2 modulate 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

Fig. 2

Metabolic reprogramming in pancreatic cancer cells. KRAS activation and mutant TP53 enhance glucose metabolism to provide biosynthetic precursors for anabolic pathways, including the non-oxidative arm of the pentose phosphate pathway (PPP) and the hexosamine biosynthesis pathway (HBP). KRAS activation reprograms glutamine metabolism to sustain cellular redox homeostasis by increasing the NADPH/NADP⁺ ratio and recycling glutathione (GSH) via reduction of oxidized GSH. The BCAT2-mediated BCAA catabolism driven by KRAS plays a critical role during pancreatic cancer development. Enhanced nutrient salvaging, via the induction of macropinocytosis and autophagy, provides energy and regenerative nutrients, including glucose, amino acids, lipids, and nucleosides

Fig. 3

Immune evasion orchestrated by pancreatic cancer cells and stromal cells. The secretion and immunomodulation of pro-tumorigenic cytokines by pancreatic cancer cells and stromal cells are tightly regulated by oncogenic KRAS- or mutant TP53-dependent pathways. Pancreatic cancer cells secrete cytokines and, chemokines and recruit immunosuppressive cells, including MDSCs, TAMs, Treg cells, and neutrophils, which suppress the activity and functions of CD8⁺ cytotoxic T cells. Pancreatic cancer cells also evade the immune system by expressing PDL-1 to promote CD8⁺ T cell exhaustion. Immune cell infiltration also releases cytokines and growth factors that directly stimulate tumor growth by promoting angiogenesis and increasing the invasive ability of pancreatic cancer cells

Fig. 4

Current clinical strategies in pancreatic cancer. For patients with pancreatic cancer, the primary clinical strategies rely on chemotherapy, whereas novel therapeutic agents targeting DNA repair, gene mutations, tumor metabolism, tumor microenvironments, or immune checkpoints might improve their prognosis. Currently, increasing interest has emerged in combined chemotherapy and immunotherapy or targeted therapy