Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma

Abstract

The malignant progression of pancreatic ductal adenocarcinoma (PDAC) is accompanied by a profound desmoplasia, which forces proliferating tumor cells to metabolically adapt to this new microenvironment. We established the PDAC metabolic signature to highlight the main activated tumor metabolic pathways. Comparative transcriptomic analysis identified lipid-related metabolic pathways as being the most highly enriched in PDAC, compared with a normal pancreas. Our study revealed that lipoprotein metabolic processes, in particular cholesterol uptake, are drastically activated in the tumor. This process results in an increase in the amount of cholesterol and an overexpression of the low-density lipoprotein receptor (LDLR) in pancreatic tumor cells. These findings identify LDLR as a novel metabolic target to limit PDAC progression. Here, we demonstrate that shRNA silencing of LDLR, in pancreatic tumor cells, profoundly reduces uptake of cholesterol and alters its distribution, decreases tumor cell proliferation, and limits activation of ERK1/2 survival pathway. Moreover, blocking cholesterol uptake sensitizes cells to chemotherapeutic drugs and potentiates the effect of chemotherapy on PDAC regression. Clinically, high PDAC Ldlr expression is not restricted to a specific tumor stage but is correlated to a higher risk of disease recurrence. This study provides a precise overview of lipid metabolic pathways that are disturbed in PDAC. We also highlight the high dependence of pancreatic cancer cells upon cholesterol uptake, and identify LDLR as a promising metabolic target for combined therapy, to limit PDAC progression and disease patient relapse.is one of the deadliest cancers, rated as the fourth leading cause of cancerrelated death in the United States and Europe, with a 5-y survival rate of about 4% and a median survival of less than 6 mo (1). In the absence of early warning signs, only 15% of patients with localized PDAC can be cured by surgical resection. For the remaining patients diagnosed with late-stage pancreatic cancer with metastatic disease, the current chemotherapy with gemcitabine (GEM) is mainly palliative and remains the standard treatment despite limited benefits (5.6-mo survival) (2). Recent advances in treatment, such as combined regimens using fluorouracil, leucovorin, irinotecan, and oxaliplatin, or Nab-paclitaxel plus GEM, conferred a survival advantage compared with GEM alone (2).The low response rate to chemotherapy is a result, in part, to the presence of a dense stroma, characterized by fibrillar networks around tumoral cells that compress vasculature and limit oxygen, nutrient, and drug delivery to the cells. A fundamental feature of tumoral cells is that they undergo metabolic reprogramming in response to these environmental constraints. Advances in tumor metabolism research reveal that PDAC cells primarily rely on glucose and glutamine catabolism to fulfill bioenergetic need and provide macromolecules required for growth and proliferation (3-5). However, metabolic reprogramming is a complex...

LDL Receptor: An open route to feed pancreatic tumor cells

“…7 Our metabolic screening revealed an undeniable contribution of lipids to the impaired metabolic network encountered in PDAC, with a high enrichment of activated-pathways associated with cholesterol-and lipoproteinrelated metabolisms, and with retinoic acid, glycosphingolipid, phosphatidylinositol, leukotriene, and steroid metabolism. 7,8 In contrast, regulation of fatty acid (FA) metabolic pathways in PDAC appears to be more complex than that of lipoproteins. Long-chain FA synthesis, transport, and desaturation are downregulated in PDAC, suggesting that these FAs come preferentially from an exogenous source.…”

“…Ldlr transcripts are selectively overexpressed in both well-differentiated and de-differentiated cancer cells that express epithelial-to-mesenchymal transition markers. 7 The foldincrease of Ldlr protein in PDAC compared to control pancreas is largely superior to that of the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr), suggesting that cholesterol uptake prevails over the cholesterol synthesis pathway (Fig. 1).…”

“…1). 7 Therefore, the massive accumulation of cholesterol in PDAC, revealing the marked dependency of pancreatic tumor cells on cholesterol, is mainly the result of an increase in exogenous cholesterol supply. We next demonstrated that disruption of Ldlr-dependent cholesterol entry through Ldlr knockdown induces an imbalance in cholesterol homeostasis by inverting the ratio of free cholesterol (FC; i.e., membrane constituent cholesterol) and cholesteryl ester (CE; i.e., stored form in lipid droplets).…”

“…Indeed, the FC content overcomes the CE stores. 7 As a consequence, FC overload drastically impairs the proliferation and tumorigenic capacities of pancreatic cancer cells and inhibits the ERK-dependent survival pathway.…”

“…Using preclinical models, we proved that metabolic weakening of pancreatic tumor cells through disruption of the physiologic balance between FC and CE content potentiates the tumor regression induced by gemcitabine. 7 From a clinical aspect, we present LDLR as a promising metabolic marker for diagnosis of patients with a high risk of recurrence, since elevated LDLR expression is correlated with an increased rate of relapse in patients with PDAC. 7 Hence, treatments targeting LDLR in this patient group could delay the time to the first relapse occurrence and consequently improve patient survival.…”