title: Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in western countries, with a median survival of 6 months and an extremely low percentage of long-term surviving patients. KRAS mutations are known to be a driver event of PDAC, but targeting mutant KRAS has proved challenging. Targeting oncogene-driven signalling pathways is a clinically validated approach for several devastating diseases. Still, despite marked tumour shrinkage, the frequency of relapse indicates that a fraction of tumour cells survives shut down of oncogenic signalling. Here we explore the role of mutant KRAS in PDAC maintenance using a recently developed inducible mouse model of mutated Kras (Kras(G12D), herein KRas) in a p53(LoxP/WT) background. We demonstrate that a subpopulation of dormant tumour cells surviving oncogene ablation (surviving cells) and responsible for tumour relapse has features of cancer stem cells and relies on oxidative phosphorylation for survival. Transcriptomic and metabolic analyses of surviving cells reveal prominent expression of genes governing mitochondrial function, autophagy and lysosome activity, as well as a strong reliance on mitochondrial respiration and a decreased dependence on glycolysis for cellular energetics. Accordingly, surviving cells show high sensitivity to oxidative phosphorylation inhibitors, which can inhibit tumour recurrence. Our integrated analyses illuminate a therapeutic strategy of combined targeting of the KRAS pathway and mitochondrial respiration to manage pancreatic cancer.
authors.affiliation: 1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3].
authors.forename: Andrea
authors.initials: A
authors.lastname: Viale
authors.affiliation: 1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3].
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Pettazzoni
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Costas A
authors.initials: CA
authors.lastname: Lyssiotis
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Haoqiang
authors.initials: H
authors.lastname: Ying
authors.affiliation: 1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Sánchez
authors.affiliation: 1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Marchesini
authors.affiliation: 1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3] Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Carugo
authors.affiliation: 1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Tessa
authors.initials: T
authors.lastname: Green
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Sahil
authors.initials: S
authors.lastname: Seth
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Giuliani
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Kost-Alimova
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Muller
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Simona
authors.initials: S
authors.lastname: Colla
authors.affiliation: 1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Nezi
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Giannicola
authors.initials: G
authors.lastname: Genovese
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Angela K
authors.initials: AK
authors.lastname: Deem
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Avnish
authors.initials: A
authors.lastname: Kapoor
authors.affiliation: 1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Wantong
authors.initials: W
authors.lastname: Yao
authors.affiliation: Pathology Unit, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Brunetto
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Ya'an
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Yuan
authors.affiliation: Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Y Alan
authors.initials: YA
authors.lastname: Wang
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffernan
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Alec C
authors.initials: AC
authors.lastname: Kimmelman
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Fleming
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.affiliation: 1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Giulio F
authors.initials: GF
authors.lastname: Draetta
mesh_terms: D000818:Animals; D001343:Autophagy; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019069:Cell Respiration / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53 / Q000235:genetics; D006019:Glycolysis; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction
chemical_list: C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)