Development of cancer is typically a multi-step process that depends on many genetic and epigenetic alterations in the tumor cells. In addition, cancer progression is modulated by interactions between the tumor cells and extracellular growth signals. This application investigates how genetic alterations and specific extracellular growth signals interact to modulate tumor progression. Mammalian cells that acquire a single activated oncogene frequently enter a state of irreversible proliferation arrest, called senescence. This """"""""oncogene-induced senescence"""""""" acts an important tumor suppression process, by arresting proliferation of nascent tumor cells and therefore preventing their progression along a tumorigenic pathway. Formation of several cancers is suppressed by this mechanism, including human melanomas, human prostate cancer, T-cell lymphomas in mice and, likely, colon cancers. Most strikingly, benign human nevi (moles) are pre-neoplastic lesions comprised of melanocytes, made senescent by oncogenic activation of the Ras-signaling pathway. In mammalian tissues, the canonical Wnt-signaling pathway typically maintains cell proliferation, for example of adult tissue stem cells. This pathway is activated by extracellular Wnt ligands that trigger a cascade of cytoplasmic and nuclear events, culminating in expression of proliferative genes. Recently, we found that Wnt-signaling antagonizes oncogene-induced senescence, and vice versa. This points to a previously unappreciated cross-talk between these two very important cell proliferation- control processes, both of great significance to cancer. In particular, these results suggest that extracellular growth signals, such as canonical Wnt ligands, can modulate cancer progression by affecting the efficiency of oncogene-induced senescence and its resultant tumor suppression activity. We will test these ideas through the following Specific Aims:
Specific Aim 1. Define how Wnt-signaling suppresses oncogene-induced senescence.
Specific Aim 2. Investigate whether Wnt-signaling drives melanoma formation by inhibiting oncogene- induced senescence in melanocytes.
Specific Aim 3. Investigate whether Wnt-signaling drives colon cancer by inhibiting oncogene-induced senescence in colonic epithelial cells.

Public Health Relevance

Recently, we found that Wnt signaling (tumor-promoting) suppresses oncogene-induced senescence (tumor-suppressing). We will test whether this new-found functional interaction contributes to tumor progression in vivo. Specifically, we will focus on melanoma and colon cancer, two cancers which between them kill about 60,000 people a year in the United States.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129334-03
Application #
7810637
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Watson, Joanna M
Project Start
2008-05-01
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
3
Fiscal Year
2010
Total Cost
$147,308
Indirect Cost
Name
University of Glasgow
Department
Type
DUNS #
229076096
City
Scotland
State
Country
United Kingdom
Zip Code
G12 8-QQ
Pawlikowski, Jeffrey S; Brock, Claire; Chen, Sheau-Chiann et al. (2015) Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling. J Invest Dermatol 135:2093-2101
Pawlikowski, Jeff S; Adams, Peter D; Nelson, David M (2013) Senescence at a glance. J Cell Sci 126:4061-7
Pawlikowski, Jeff S; McBryan, Tony; van Tuyn, John et al. (2013) Wnt signaling potentiates nevogenesis. Proc Natl Acad Sci U S A 110:16009-14
Banumathy, Gowrishankar; Somaiah, Neeta; Zhang, Rugang et al. (2009) Human UBN1 is an ortholog of yeast Hpc2p and has an essential role in the HIRA/ASF1a chromatin-remodeling pathway in senescent cells. Mol Cell Biol 29:758-70
Adams, Peter D; Enders, Greg H (2008) Wnt-signaling and senescence: A tug of war in early neoplasia? Cancer Biol Ther 7:1706-11
Sedivy, John M; Banumathy, Gowrishankar; Adams, Peter D (2008) Aging by epigenetics--a consequence of chromatin damage? Exp Cell Res 314:1909-17