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Carugo, Alessandro

Chen, Shujuan

Chen, Ziheng

Draetta, Giulio

Feng, Ningping

Gay, Jason P

Genovese, Giannicola

Ho, I-Lin

Marszalek, Joeeph

Rose, Johnathon L

Soeung, Melinda

Srinivasan, Sanjana

Viale, Andrea

Yan, Liang

Yao, Wantong, MD, PhD

Ying, Haoqiang

English

OpenWorks @ MD Anderson

Ether phospholipids metabolism is required for mitochondrial ROS homeostasis in pancreatic cancerBackgroundTargeting mitochondrial complexes is emerging as aneffective chemotherapy strategy, prompting theurgency to better understand drug resistance tomitochondrial complex inhibitors. Here we report thatintrinsic lipid metabolism contributes to resistancewhen targeting mitochondrial complex I in pancreaticductal adenocarcinoma (PDAC). Our data indicatesthat induction of mitochondrial- and lipid- reactiveoxidative species (ROS) is critical for complex Iinhibition induced cell death. Lipidomic analysisrevealed an abundance of ether-formed mono-unsaturated fatty acids (MUFAs), in cells resistant tocomplex I inhibition, is an essential fuel for ROSscavenging. Blocking ether-MUFAs by knocking outenzymes responsible for ether-formed phospholipidsgeneration in peroxisome, sensitized resistant cells.Together, our findings uncovered a novel adaptivemechanism dependent on ether-lipids metabolismbased on the peroxisome-mitochondria network thatis responsible for PDAC resistance to OXPHOSinhibition, providing the rationale for combinatorystrategies to target mitochondria in PDAC.Result 1: Sensitive & Resistant response to mitochondrial CI inhibitor in PDACsResult2: Mitochondrial ROS scavenging contributes to PDAC resistance Result3: Ether-lipid metabolism is crucial for PDAC resistanceHypothesis modelReferencesZiheng Chen1, I-Lin Ho1, Jintan Liu1, Liang Yan3, Shujuan Chen3, Melinda Soeung1, Johnathan Rose1, Sanjana Srinivasan1, Andrea Viale1, Alessandro Carugo2, Giannicola Genovese4, Wantong Yao5, Ningping Feng2, Jason Gay2, Joseph Marszalek2, Haoqiang Ying3, Giulio Draetta1,31Department of Genomic Medicine, 2Institute for Applied Cancer Science, 3Department of Molecular and Cellular oncology, 4Department of Genitourinary Medical Oncology,5Department of Translational Molecular Pathology , The University of Texas MD Anderson Cancer Center, University of Texas, 77030(A) Lipidomics analysis showed more ether modified MUFAs inresistant lines than in sensitive lines. Mitochondrial ROS (B) and celldeath (C) detection upon 3-days treatment of 10nM IACS-010759 inEther generation deficiency by blocking GNPAT signaling. (D) Xenografttumor growth of sgCTRL/sgGNPAT with or without 5mpk IACS-010759.Tumor volume was measured at the days indicated. (E) Cell deathevents in sgCTRL, sgGNPAT PDAC with ether- linked MUFA (C16-18:1PC). *P<0.05, **P<0.01, ***P<0.001.Sensitive and Resistant PATC lines were treated with 10nM IACS-10759 in3 days. Mitochondrial ROS were detected by MitoSOX Dye. (C) H2O2indicator showed ROS production with 10nM IACS-010759 in indicatedtime. Anti-TOMM2O reflected mitochondrial location. Scale bar, 10um.Mitochondrial-ROS inducer MitoPQ (C) and scavenger mitoQ(D) and SOD2deficiency (E) affect PDAC resistance.Sensitive (A) and Resistant (B) PATC lines generated Xenograft tumorswere treated with or without 5mpk IACS-010759 in 3 days. Tumorvolume was measured at the days indicated. (C) IHC for apoptoticmarker Caspase 3 in PATCs subcutaneous tumors with or without 5mpkIACS-010759 5mpk. H&E staining is shown. Scale bar, 50um.1. Molina JR, Sun Y, et al. An inhibitor of oxidative phosphorylation exploits cancervulnerability. Nat Med. 2018 Jul; 24(7):1036-1046.2. Farge T, Saland E, et al. Chemotherapy-Resistant Human Acute Myeloid LeukemiaCells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism.Cancer Discov. 2017 Jul; 7(7):716-735.3. Iwamoto H, Abe M, et al. Cancer Lipid Metabolism Confers Antiangiogenic DrugResistance. Cell Metab. 2018 Jul 3; 28(1):104-117.e5.4. Elgendy M, Cirò M, et al. Combination of Hypoglycemia and Metformin ImpairsTumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1Axis. Cancer Cell. 2019 May 13; 35(5):798-815.e5.A BCA BC D EABCD ECartoon working model. Ether linked- MUFAs generated throughperoxisome and mitochondria contribute to complex I inhibition byscavenging mitochondrial- and lipid-ROS.

Ether phospholipids metabolism is a latent vulnerability for pancreatic cancer resistance

https://openworks.mdanderson.org/cgi/viewcontent.cgi?article=1062&amp;context=leading-edge

Ether phospholipids metabolism is a latent vulnerability for pancreatic cancer resistance

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