Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy

Abstract

Background KRAS is the predominant oncogene mutated in pancreatic ductal adenocarcinoma (PDAC), the fourth cause of cancer-related deaths worldwide. Mutant KRAS-driven tumors are metabolically programmed to support their growth and survival, which can be used to identify metabolic vulnerabilities. In the present study, we aimed to understand the role of extracellularly derived fatty acids in KRAS-driven pancreatic cancer. Methods To assess the dependence of PDAC cells on extracellular fatty acids we employed delipidated serum or RNAi-mediated suppression of ACSL3 (to inhibit the activation and cellular retention of extracellular fatty acids) followed by cell proliferation assays, qPCR, apoptosis assays, immunoblots and fluorescence microscopy experiments. To assess autophagy in vivo, we employed the KrasG12D/+;p53flox/flox;Pdx1-CreERT2 (KPC) mice crossed with Acsl3 knockout mice, and to assess the efficacy of the combination therapy of ACSL3 and autophagy inhibition we used xenografted human cancer cell-derived tumors in immunocompromised mice. Results Here we show that depletion of extracellularly derived lipids either by serum lipid restriction or suppression of ACSL3, triggers autophagy, a process that protects PDAC cells from the reduction of bioenergetic intermediates. Combined extracellular lipid deprivation and autophagy inhibition exhibits anti-proliferative and pro-apoptotic effects against PDAC cell lines in vitro and promotes suppression of xenografted human pancreatic cancer cell-derived tumors in mice. Therefore, we propose lipid deprivation and autophagy blockade as a potential co-targeting strategy for PDAC treatment. Conclusions Our work unravels a central role of extracellular lipid supply in ensuring fatty acid provision in cancer cells, unmasking a previously unappreciated metabolic vulnerability of PDAC cells.

In Pancreatic Adenocarcinoma Alpha-Synuclein Increases and Marks Peri-Neural Infiltration

“…Moreover, α-syn relays on the autophagy pathway for its clearance [ 69 , 70 ]. In line with this, the autophagy pathway is altered in PDAC [ 41 , 71 ]. Little is known about a potential cancerogenic role of α-syn, and no study is, to date, available for PDAC.…”

“…This is very important considering that α-syn is removed by autophagy [ 40 ]. Since an alteration of autophagy machinery in PDAC occurs [ 41 ], it is expected that autophagy-dependent proteins may be altered consistently. Among these proteins, α-syn may be useful to improve diagnostic tools in PDAC.…”

Cellular metabolism in pancreatic cancer as a tool for prognosis and treatment (Review)

“…Finally, to be able to cope with a situation when nutritional deficiencies arise, PDAC cells are well-adapted to take advantage of extracellular nutrient sources available in the microenvironment. When needed, they can utilize protein-macropinocytosis to obtain important amino acids by lysosomal degradation, as well as autophagy to recycle proteins, macromolecules and whole organelles and to refill essential nucleotide pools (139)(140)(141)(142)(143). Additionally, autophagy in PC supports immune evasion and is required for proper cystine transport and cysteine homeostasis by promoting the localization of the cystine transporter SLC7A11 at the plasma membrane (144,145).…”

Metabolic Pathways as a Novel Landscape in Pancreatic Ductal Adenocarcinoma

“…ACSL3 activity, a protein-coding gene for a member of Acyl-CoA synthetase long-chain family, has been linked to KRAS-mutated tumors [ 127 ] and associated with the retention of extracellular unsaturated FAs by converting them into esters that remain confined in PDAC cells [ 128 , 129 ]. Serum lipid depletion or ACSL3 inhibition decreased tumor cell proliferation, provoking a rebound effect due to lipid restriction that was balanced by increased autophagic flux, in both in vitro and in vivo models [ 130 ]. Notably, combining lipid depletion with autophagy inhibitors induced the most potent effect, with arrest of PDAC proliferation and increased apoptosis [ 130 ].…”

“…Serum lipid depletion or ACSL3 inhibition decreased tumor cell proliferation, provoking a rebound effect due to lipid restriction that was balanced by increased autophagic flux, in both in vitro and in vivo models [ 130 ]. Notably, combining lipid depletion with autophagy inhibitors induced the most potent effect, with arrest of PDAC proliferation and increased apoptosis [ 130 ]. Recently, metabolomic profiles clarified key aspects of the metabolic signature of pancreatic cancer stem cells (PCSCs) originating from PDAC cells, revealing a fundamental role for the pyruvate–malate cycle and lipid metabolism in their survival [ 131 ].…”