Novel strategy for oncogenic alteration-induced lipid metabolism reprogramming in pancreatic cancer

Abstract

The pathogenesis of pancreatic cancer involves substantial metabolic reprogramming, resulting in abnormal proliferation of tumor cells. This tumorigenic reprogramming is often driven by genetic mutations, such as activating mutations of the KRAS oncogene and inactivating or deletions of the tumor suppressor genes SMAD4, CDKN2A, and TP53, which play a critical role in the initiation and development of pancreatic cancer. As a normal cell gradually develops into a cancer cell, a series of signature characteristics are acquired: activation of signaling pathways that sustain proliferation; an ability to resist growth inhibitory signals and evade apoptosis; and an ability to generate new blood vessels and invade and metastasize. In addition to these features, recent research has revealed that metabolic reprogramming and immune escape are two other novel characteristics of tumor cells. The effect of the interactions between tumor and immune cells on metabolic reprogramming is a key factor determining the antitumor immunotherapy response. Lipid metabolism reprogramming, a feature of many malignancies, not only plays a role in maintaining tumor cell proliferation but also alters the tumor microenvironment by inducing the release of metabolites that in turn affect the metabolism of normal immune cells, ultimately leading to the attenuation of the antitumor immune response and resistance to immunotherapy. Pancreatic cancer has been found to have substantial lipid metabolism reprogramming, but the mechanisms remain elusive. Therefore, this review focuses on the mechanisms regulating lipid metabolism reprogramming in pancreatic cancer cells to provide new therapeutic targets and aid the development of new therapeutic strategies for pancreatic cancer.

Keywords: drug resistance; immune escape; lipid metabolism reprogramming; pancreatic cancer; tumor microenvironment.

Figure 1

Oncogenic mutations and regulatory mechanisms in the development of pancreatic cancer

Figure 2

KRAS mutations in pancreatic cancer are involved in many biological processes On one hand, through the downstream RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways, KRAS mutations increase the proliferation and survival ability of pancreatic cancer cells, contributing to immune escape and drug resistance and leading to metabolic reprogramming. On the other hand, various substances secreted by pancreatic cancer cells caused by KRAS mutations change the tumor immune microenvironment (substances such as IL-4, IL-6, IL-10, IL-13, KrasG12D protein, TGF-β, MCP-1, CSF-1, and CCL2) and extracellular matrix structure (such as Hedgehog ligand and TGF-β) and contribute to tumor angiogenesis (such as VEGF).

Figure 3

Gene mutations cause reprogramming of lipid metabolism in pancreatic cancer cells to meet their proliferation needs This is reflected in the increased de novo synthesis of fatty acids, enhanced activities of various rate-limiting enzymes, and upregulated expression of receptors for transporting exogenous cholesterol and lipid droplets. The synthesized lipids satisfy the proliferation and survival of pancreatic cancer and signal transduction.

Figure 4

Excessive lipid accumulation in the tumor microenvironment of pancreatic cancer attenuates the antitumor immune response First, the upregulation of various enzymes related to lipid metabolism affects the function of immune cells, including the following aspects: overexpression of ACC and FASN can promote the differentiation of Th17 cells, inhibit the differentiation of Treg cells and promote tumor progression; CD36 and LDLR translocate excessive fatty acids and cholesterol into cells, activate fatty acid β-oxidation, inhibit the secretion of TNF-α and IFN-γ cytokines by CD8 + T cells, and weaken the antitumor response; and the increased expressions of CPT1A, FAS, SCD1 and other enzymes can change the lipid type or trigger the accumulation of intracellular lipid droplets, thereby affecting the status and function of immune cells. Second, tumor cells secrete PEG2 to promote the transformation of M1-type macrophages into M2-type macrophages, and PEG2 activates the cAMP-PKA signaling pathway, leading to the growth arrest of CD8 + T cells and the antitumour activity of Tregs and DCs. Tumor cells can also secrete lactic acid to cause intracellular acidification of NK cells, inhibit the secretion of IFN-γ, and promote NK cell apoptosis. Excessive lipid accumulation leads to antigen presentation dysfunction in DCs, which in turn fails to activate primary T cells and ultimately reduces the antitumour immune response. Pancreatic cancer cells activate the B-cell surface receptor CD40, and B cells secrete IL-35 to promote tumor cell proliferation. Pancreatic cancer can also recruit TAMs through the CCL2/CCR2 chemokine axis, resulting in decreased secretion of proinflammatory factors such as IFN-β and IL-1β, which in turn causes insufficient recruitment of effector T cells and NK cells and builds an immunosuppressive tumor microenvironment. Increased CPT1A expression in macrophages promotes fatty acid transport into mitochondria, promotes β-oxidation, and inhibits macrophage secretion of the proinflammatory factors IFN-β and IL-1β.