The critical roles of activated stellate cells-mediated paracrine signaling, metabolism and onco-immunology in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant diseases worldwide. It is refractory to conventional treatments, and consequently has a documented 5-year survival rate as low as 7%. Increasing evidence indicates that activated pancreatic stellate cells (PSCs), one of the stromal components in tumor microenvironment (TME), play a crucial part in the desmoplasia, carcinogenesis, aggressiveness, metastasis associated with PDAC. Despite the current understanding of PSCs as a "partner in crime" to PDAC, detailed regulatory roles of PSCs and related microenvironment remain obscure. In addition to multiple paracrine signaling pathways, recent research has confirmed that PSCs-mediated tumor microenvironment may influence behaviors of PDAC via diverse mechanisms, such as rewiring metabolic networks, suppressing immune responses. These new activities are closely linked with treatment and prognosis of PDAC. In this review, we discuss the recent advances regarding new functions of activated PSCs, including PSCs-cancer cells interaction, mechanisms involved in immunosuppressive regulation, and metabolic reprogramming. It's clear that these updated experimental or clinical studies of PSCs may provide a promising approach for PDAC treatment in the near future.

Keywords: Drug resistance; Immune evasion; Metabolic reprogramming; PDAC; Pancreatic stellate cells.

Fig. 1

Phenotypic transition of PSCs and desmoplastic TME. qPSCs are activated by risk factors, local environmental stress, cellular and molecular regulations. During the oncogenesis, aPSCs largely contribute to fibrotic microenvironment, which is a major characteristic of PDAC. The desmoplastic TME consists of epithelial PDA cells and numerous stromal components, such as immunosuppressive cells, aPSCs, collagens and so on

Fig. 2

PSCs mediate invasion, metastasis, therapeutic resistance of PDAC. Multiple factors are involved in, such as immune evasion, metabolic reprogramming, ECM remodeling, various paracrine signaling and so forth

Fig. 3

PSCs in metabolic reprogramming. In KRAS-dependent pathways, diverse cytokines and signaling pathways mediate metabolic interactions between PSCs and PDA cells. KRAS-driven glutamine (Gln) metabolism becomes a major carbon source for tumor cells survival; PSCs-derived IGF elevates mitochondrial respiration in PDA cells via IGF1R/AXL axis; KRAS-mutant PDA cells can obtain extracellular proteins for supporting growth through upregulated macropinocytosis. PSCs-secreted non-essential amino acids (NEAAs), such as autophagy-induced Ala, can serve as an alternative energy source to fuel PDA cells. In KRAS-independent pathways, PSCs-derived growth factors (GFs) and exosomes play a pivotal role in mediating survival, proliferation, metastasis, biosynthesis of tumor cells

Fig. 4

Immunosuppressive modulator role of PSCs. PSCs induce TME remodeling, dense matrix caused hypoxia and hypo-vascularity impair T cells infiltration and their nutrition obtaining; multifactorial T cell exhaustion attenuates T_eff functions; PSCs-derived suppressive factors (such as IL-6, CXCL12), suppressive signaling and recruitment of suppressive cells (such as MDSCs, T_reg cells, TAMs) create an immunosuppressive TME in PDAC