Recent insights into the biology of pancreatic cancer

Abstract

Pancreatic cancer (PDAC) is one of the deadliest types of human cancers, owing to late stage at presentation and pervasive therapeutic resistance. The extensive tumour heterogeneity, as well as substantial crosstalk between the neoplastic epithelium and components within the microenvironment are the defining features of PDAC biology that dictate the dismal natural history. Recent advances in genomic and molecular profiling have informed on the genetic makeup and evolutionary patterns of tumour progression, leading to treatment breakthroughs in minor subsets of patients with specific tumour mutational profiles. The nature and function of tumour heterogeneity, including stromal heterogeneity, in PDAC development and therapeutic resistance, are increasingly being elucidated. Deep insight has been gained regarding the metabolic and immunological deregulation, which further sheds light on the complex biology and the observed treatment recalcitrance. Here we will summarize these recent achievements and offer our perspective on the path forward.

Keywords: Cancer metabolism; Evasion; Genetics; Immune; Immunotherapy; Pancreatic cancer; Ttumour heterogeneity.

Fig. 1

Metabolic reprogramming of neoplastic cells and crosstalk with the tumour microenvironment. Glucose uptake and glycolysis are activated in PDAC cells, which promotes the flux of glycolysis intermediates into biosynthetic pathways, including pentose phosphate pathway and hexose biosynthesis pathway, for the production of nucleic acid and glycan structures, amongst others. Tumour cells also uptake circulating lactate, which is further fed into TCA cycle through yet unknown mechanisms. Glutamine metabolism in PDAC cells is rewired to support the production of NADPH in the cytosol to maintain redox balance. PDAC cells are characterized by enhanced nutrient salvage, including the induction of macropinocytosis and autophagy, which provide substrate for energy production and anabolism in mitochondria. Autophagy in stromal fibroblasts provides alanine, which feeds into mitochondrial TCA cycle in tumour cells. Amino acids are also transferred from fibroblasts to tumour cells through exosomes. In addition, stromal fibroblasts provide phospholipids to support the proliferation of tumour cells. Tumour-associated macrophages excrete pyrimidines, in particular deoxycytidine, which competitively inhibit DCK in tumour cells to prevent gemcitabine activation and thus leading to chemoresistance. CAFs: cancer-associated fibroblasts; LPC: lysophosphatidylcholine; LPA: lysophosphatidic acid; TAMs: tumour-associated macrophages; DCK: deoxycytidine kinase; PPP: pentose phosphate pathway; HBP: hexose biosynthesis pathway; ROS: reactive oxygen species.

Fig. 2

Immune evasion orchestrated by tumour cells and the tumour microenvironment. PDAC cells release cytokines and recruit immunosuppressive cells, including myeloid cells, regulatory T cells and γδT cells, which inhibit the function of effector T cells. Tumour cells also promote the activation of stromal fibroblasts by producing ligands, such as SHH. Activated fibroblasts not only enhance the growth of tumour cells, but also inhibit effector T cells through several different mechanisms, including the deposition of extracellular matrix to impede T cell trafficking, excretion of cytokines to suppress T cells activity, and induction of immunosuppressive myeloid cells directly with cytokines or indirectly through the recruitment of suppressive B cells. Some of the immune infiltrates, including suppressive B cells and myeloid cells, also produce growth factor ligands or cytokines to directly stimulate tumour growth. Metabolite changes in the tumour microenvironment also contribute to the inhibition of T cell activation, including depletion of glucose, arginine and tryptophan and the accumulation of lactate and kynurenine. Treg: regulatory T cells, ECM: extracellular matrix, CAFs: cancer-associated fibroblasts, Teff: effector T cells, MDSC: myeloid-derived suppressor cell; TAM: tumour-associated macrophage.