Michigan Cancer Research Fund                                                                                            American Cancer Society
   
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Research Project Description and Objectives from Jennifer Speth, PhD, MCRF 2017 Fellow

Project Name: Defining the Role of Alveolar Macrophage Secreted SOC3 in Lung Cancer

Lung cancer is the leading cancer killer in both men and women and has a five-year survival rate of only 18%. The majority of lung cancers arise from epithelial cells which are the structural cells that line the inside of the lung. Homeostatis is the balanced state where everything functions normally; lung cancer is thought to develop as a result of altered homeostasis and unrestrained inflammation in the lung environment. In the normal lung, homeostasis is maintained by communication between epithelial cells and the resident immune cell of the lung, the alveolar macrophage. The alveolar macrophage functions as the patroller or security guard in the lung. The alveolar macrophage communicates with epithelial cells to send signals to other cells when help is needed to clear infection, so it is very important that they communicate effectively to each other to manage the immune response effectively.

Recently, our lab discovered a novel type of communication in which alveolar macrophages release small “packages” termed microvesicles that contain a suppressive protein termed SOCS3. These vesicles can be taken up by epithelial cells and result in inhibition of inflammatory responses. In lung cancer, it is thought that low levels of SOCS3 within epithelial cells can promote inflammation and tumor formation. We speculate that acquisition of SOCS3 from alveolar macrophages may represent a “backup” source of this tumor suppressor in epithelial cells, but whether this process is disrupted in lung cancer is not known. Our preliminary data suggest that it is.

In my project, we will:

  • verify and determine the mechanisms of dysregulated alveolar macrophage SOCS3 secretion in lung cancer
  • explore the potential use of synthetic microvesicles containing SOCS3 as a therapeutic strategy to inhibit tumor formation and progression, both in human cancer cells and mouse models of lung cancer
  • conduct exploratory analysis of SOCS3 levels in samples from patients undergoing diagnostic procedures for lung cancer to assess correlations with cancer cell type and stage to suggest potential future biomarker studies

Summer 2018 Update from Dr. Speth: I am presently working on structural and biochemical studies of the metastatic protein P-Rex1 towards understanding how this protein is regulated in the body, particularly in cancer metastasis, which is the project that I was working on while funded by MCRF. Since our 2016 publication on this work in the journal Structure, we have made substantial breakthroughs on this project and will submit multiple manuscripts for publication within the next year. I am currently a research investigator at the University of Michigan in the labs of John Tesmer and Michael Cianfrocco where I am learning an exciting new technique called cryo-electron microscopy in order to address “bigger picture” questions on this project. Our labs just recently received and NIH R01 to continue this work. Right now, I am on the job market for a faculty position to start up my own lab, where I will be taking this project with me as well as pursuing other related projects focusing on cancer-implicated proteins and understanding regulation of their functions in the body. Having something as prestigious as an ACS-MCRF postdoctoral fellowship on my record has been very helpful in applying for these positions.