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Metz, Heather (2016) NON-CANONICAL ROLE FOR INSULIN RECEPTOR SUBSTRATE-1 IN SIGNALING PATHWAYS OF THE LUNG. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Lung cancer is the leading cause of cancer deaths worldwide. In the United States alone, lung cancer accounts for ~160,000 deaths per year while the five-year survival rate remains stagnant at ~15%. Lung can be divided into different subsets including small cell and non-small cell lung cancer. Lung Adenocarcinoma (ADCA) accounts for over 50% of non-small lung cancer cases. Within this subset, KRAS is the most common activating mutation, accounting for ~35% of cases. KRAS mutant tumors have remained a largely un-targetable subtype, and a better understanding of the signaling pathways involved in the different ADCA subtypes will be necessary for the development of therapeutics. Insulin Receptor Substrate-1 (IRS-1) is a signaling adaptor protein that interfaces with many of the pathways that are activated in lung cancer, including phosphoinositol 3-kinase (PI3K), extracellular signal regulated kinase (MEK/ERK) and Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT). The central theme of this work is to describe novel roles for IRS-1 in the lung, including its integral role in the interplay between tumor cells and the surrounding tumor microenvironment. A key player in this interaction is the neutrophil, which can have pro-host and pro-tumor roles. We have found that neutrophils present in the tumor microenvironment cause degradation of the intracellular protein IRS-1, which in turn increases PI3K pathway activation leading to increased tumor proliferation. Independent study of IRS-1 loss with an Irs-1-deficient mouse model showed that Irs-1 loss induces an increase in neutrophil recruitment to the tumor. These two observations reveal a self-perpetuating cycle that causes increased tumor burden and mortality in mice and humans. Loss of Irs-1 in our Kras mouse model of lung adenocarcinoma induced activated JAK/STAT signaling and induced recruitment of immune cells to the tumor. Since neutrophils are essential for protection against invading pathogens, an indirect method of stopping this cycle must be used. Inhibiting JAK in our mouse model reduced inflammation, which in turn reduced tumor burden and prolonged survival. Overall, this work describes a novel role for IRS-1 as a mediator of cell growth and immune cell recruitment in lung adenocarcinoma.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Metz, Heatherhem5@pitt.eduHEM5
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMars, Wendy M.wmars@pitt.eduWMARS
Thesis AdvisorHoughton, A
Committee MemberDeFrances,
Committee MemberO'Doherty, Robert Mrmo1@pitt.eduRMO1
Committee MemberShapiro, Steven Dshapiros@dom.pitt.eduSDS33
Date: 20 May 2016
Date Type: Publication
Defense Date: 12 November 2015
Approval Date: 20 May 2016
Submission Date: 28 March 2016
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 144
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Lung, Cancer, IRS-1
Date Deposited: 20 May 2016 15:16
Last Modified: 20 May 2019 05:15


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