During carcinoma progression, tumor cells acquire the ability to survive and expand in absence of proper extracellular matrix (ECM) contact, which facilitates both early carcinoma formation and the later stages of dissemination and metastasis. Integrin-mediated cell adhesion to ECM is critical for normal epithelial cell survival;in fact, ECM-deprived normal cells (unlike cancer cells) undergo apoptosis, termed anoikis. Constitutive growth factor pathway activation is a common mechanism utilized by cancer cells to evade anoikis. Oncogenes that activate key growth factor signals, such as the Ras/MAPK and PI3K/Akt pathways, protect cancer cells from death. However, we recently discovered that another mechanism protects epithelial cells during anoikis-autophagy. Autophagy is a tightly regulated self-digestion process that promotes cell survival during starvation and stress. Interestingly, in follow-up studies, we have found that autophagy is robustly induced in detached cells expressing oncogenes that activate either PI3K/Akt or Ras/MAPK. Based on these findings, we hypothesize that autophagy is required for oncogenic cells survival when deprived of adhesion dependent ECM contact. We will test this hypothesis through three specific aims.
In Aim 1, we will determine how oncogenes regulate detachment-induced autophagy and whether autophagy promotes the survival of oncogene-expressing cells during anoikis and 3D morphogenesis.
In Aim 2, we will identify the signals through which ECM detachment induces autophagy.
In Aim 3, we will define the tumor promoting vs. suppressive functions of autophagy in cancer cells during oncogenic transformation and adhesion independent survival. Since autophagy is regulated by a defined set of genes (called ATGs), distinct from established apoptosis regulators, our studies may reveal unique mechanisms and pathways to exploit against human carcinomas.

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 #
1R01CA126792-01A2
Application #
7578367
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mohla, Suresh
Project Start
2009-02-01
Project End
2014-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
1
Fiscal Year
2009
Total Cost
$283,732
Indirect Cost
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
Monkkonen, Teresa; Debnath, Jayanta (2018) Inflammatory signaling cascades and autophagy in cancer. Autophagy 14:190-198
Cadwell, Ken; Debnath, Jayanta (2018) Beyond self-eating: The control of nonautophagic functions and signaling pathways by autophagy-related proteins. J Cell Biol 217:813-822
Roy, Srirupa; Debnath, Jayanta (2017) Autophagy enables retromer-dependent plasma membrane translocation of SLC2A1/GLUT1 to enhance glucose uptake. Autophagy 13:2013-2014
Vlahakis, Ariadne; Debnath, Jayanta (2017) The Interconnections between Autophagy and Integrin-Mediated Cell Adhesion. J Mol Biol 429:515-530
Rose, John C; Huang, Po-Ssu; Camp, Nathan D et al. (2017) A computationally engineered RAS rheostat reveals RAS-ERK signaling dynamics. Nat Chem Biol 13:119-126
Roy, Srirupa; Leidal, Andrew M; Ye, Jordan et al. (2017) Autophagy-Dependent Shuttling of TBC1D5 Controls Plasma Membrane Translocation of GLUT1 and Glucose Uptake. Mol Cell 67:84-95.e5
Kenific, Candia M; Debnath, Jayanta (2016) NBR1-dependent selective autophagy is required for efficient cell-matrix adhesion site disassembly. Autophagy 12:1958-1959
Liu, J; Debnath, J (2016) The Evolving, Multifaceted Roles of Autophagy in Cancer. Adv Cancer Res 130:1-53
Altshuler-Keylin, Svetlana; Shinoda, Kosaku; Hasegawa, Yutaka et al. (2016) Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance. Cell Metab 24:402-419
Kenific, Candia M; Stehbens, Samantha J; Goldsmith, Juliet et al. (2016) NBR1 enables autophagy-dependent focal adhesion turnover. J Cell Biol 212:577-90

Showing the most recent 10 out of 45 publications