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Thesis Defense

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by

Scott McDonnell

on 11 February 2013

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Transcript of Thesis Defense

Scott McDonnell
Thesis Defense
February 12, 1013 Phosphoproteomics Metabolomics Integromics The Role of PKM in ALCL tumor metabolism Conclusions Approach Background Anaplastic Large Cell Lymphoma Anaplastic Lymphoma Kinase Cancer Metabolism PKM Background Metabolic Flux Analysis Reveals ALK Driven Metabolic Switch ALK induces changes in metabolic processes 4784 Metabolites 836 Metabolites Most common pediatric peripheral T-cell lymphoma
Highly aggressive tumors
25% of patients die from recurrence RTK in the insulin receptor (IR) superfamily
Expression limited to developing neural tissue Ubiquitously expressed nucleolar protein
Functions include:
Nuclear shuttling
Ribosome biogenesis
Histone charperone assembly Nucleophosmin ALK Oncogenic Translocations NPM-ALK Oncogene t(2;5)(p23;q35) Results in aberrant expression, localization, activation Warburg Effect Approach The Role of NPM-ALK Signaling in
Tumor Cell Metabolism Acknowledgments Lab Members Family and Friends Identification of PKM by phosphoproteomics PKM in Glycolysis Regulation PKM Isoforms and Regulation Hypothesis: NPM-ALK inhibits PKM altering metabolism and promoting tumorigenesis NPM-ALK phosphorylates Y105-PKM NPM-ALK inhibits PKM activity PKM mediates ALK driven metabolic switch Y105-PKM regulates activity PKM regulates ALCL proliferation and metabolism PKM regulates ALCL colony formation PKM regulates ALCL tumor formation University of Michigan Validation of phosphoproteomic conditions ALK induces global phosphoproteomic changes Biological information flow ALK induces global metabolic changes Metabolic pathway analysis reveals changes in biomass producing pathways NPM-ALK induces global metabolic changes to drive biomass production
PKM is a novel substrate of ALK and mediates the metabolic switch
PKM is a new therapeutic target in ALK driven cancers TATESFASDPILpYRPVAVALDTK Mentors: Collaborators:
Charles Burant
Chunhai Ruan
Alexander Raskind
Craig Thomas Pathology Department:
Nick Lukacs
Laura Labut
Laura Hessler ALK activity alters biomass associated pathways Integrated analysis highlights ALK induced metabolic signature 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2
Full transcript