Autophagy is a tightly regulated lysosomal degradation process in which a cell digests its own contents under various forms of duress. In eukaryotic cells, autophagy primarily functions as a protective response during nutrient depletion or stress. Overall, much remains to be learned about how this fundamental process affects cancer initiation, progression and response to therapy. In this proposal, we will test the hypothesis that autophagy influences epithelial cancer development through two mechanisms-1) enhancing the ability of epithelial cells to survive ECM detachment-induced stress and apoptosis (anoikis) and 2) limiting proliferation. This hypothesis is based on initial studies using a unique 3D epithelial culture system to examine how oncogenic insults affect the formation of the normally hollow lumen in glandular structures. In this model, lumen formation involves the selective death of central cells lacking direct contact with extracellular matrix (ECM). Recently, we have discovered high levels of autophagy during lumen formation, indicating that this critical process also contributes to epithelial cell fate. In subsequent work, we are the first to establish that autophagy is strongly induced during ECM deprivation (anoikis). Based on this preliminary data, in Aim 1, we will evaluate whether autophagy promotes cell survival via mitigating the stresses of ECM detachment during anoikis and 3D lumen formation. In addition, we have obtained preliminary evidence that the autophagy regulatory molecule Beclin/ATG6 (a known tumor suppressor) inhibits cell proliferation in 3D culture.
In Aim 2. we will interrogate whether other autophagy regulators (called ATGs) inhibit proliferation during growth factor withdrawal and 3D morphogenesis in order to definitively establish that autophagy can restrain epithelial proliferation and to identify new autophagy regulators that are able to inhibit neoplastic cell expansion.
In Aim 3. we will delineate how modulating autophagy influences survival and proliferation in oncogene-expressing cells in order to determine how autophagy can be exploited to therapeutically target tumor cells harboring perturbations in known cancer pathways. Overall, the proposed experiments will provide unique information on the precise roles of autophagy during the development and progression of human carcinomas. Ultimately, these studies may lead to new treatment strategies to prevent the uncontrolled expansion of cancer cells via manipulating autophagy.

Public Health Relevance

We recently discovered that autophagy is a novel survival mechanism for cells detached from extracellular matrix, a major stress faced by tumor cells during cancer progression and metastasis. Autophagy is a fundamental process in which a cell digests its own contents (i.e. literally eats itself) during times of stress. As interest in manipulating autophagy to treat cancer rapidly intensifies, our proposed studies will provide unique and timely insight into how autophagy can be exploited to kill or suppress the expansion of cancer cells detached from extracellular matrix, and thus, impede progression and metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA126792-04
Application #
8211075
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Woodhouse, Elizabeth
Project Start
2009-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$274,012
Indirect Cost
$92,864
Name
University of California San Francisco
Department
Pathology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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