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REGULATION OF ONCOGENE-INDUCED SENESCENCE BY WNT-SIGNALING

Award Number: R01CA129334
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2008
PERIOD OF PERFORMANCE END DATE: 02/29/2012

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REGULATION OF ONCOGENE-INDUCED SENESCENCE BY WNT-SIGNALING - DESCRIPTION (provided by applicant): 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2011 ( Subtotal = $195,639 )
2011	2011	UNIVERSITY OF GLASGOW	CRUK BEATSON LABORATORIES GARSCUBE	SWITCHBACK ROAD				GBR	Cancer Biology Research	001	4	5/13/2011	NON-COMPETING CONTINUATION	$14,118
2011	2011	UNIVERSITY OF GLASGOW	CRUK BEATSON LABORATORIES GARSCUBE	SWITCHBACK ROAD				GBR	Cancer Biology Research	000	4	2/23/2011	NON-COMPETING CONTINUATION	$181,521
														Subtotal = $195,639

Issue Date FY: 2010 ( Subtotal = $147,308 )
2010	2010	UNIVERSITY OF GLASGOW	CRUK BEATSON LABORATORIES GARSCUBE	SWITCHBACK ROAD				GBR	Cancer Biology Research	001	3	3/18/2010	NON-COMPETING CONTINUATION	$13,859
2010	2010	UNIVERSITY OF GLASGOW	CRUK BEATSON LABORATORIES GARSCUBE	SWITCHBACK ROAD				GBR	Cancer Biology Research	000	3	2/26/2010	NON-COMPETING CONTINUATION	$133,449
2010	2009	UNIVERSITY OF GLASGOW	UNVERSITY AVE, GLASGOW G12 8QQ	UNITED KINGDOM				GBR	Cancer Biology Research	003	2	3/18/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2010	2008	INSTITUTE FOR CANCER RESEARCH	7701 BURHOLME AVENUE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	002	1	3/18/2010	NEW	$0
														Subtotal = $147,308

Issue Date FY: 2009 ( Subtotal = $201,690 )
2009	2009	UNIVERSITY OF GLASGOW	CRUK BEATSON LABORATORIES GARSCUBE	SWITCHBACK ROAD				GBR	Cancer Biology Research	001	2	4/21/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$201,690
2009	2008	INSTITUTE FOR CANCER RESEARCH	7701 BURHOLME AVENUE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	1	4/21/2009	NEW	$0
														Subtotal = $201,690

Issue Date FY: 2008 ( Subtotal = $323,233 )
2008	2008	INSTITUTE FOR CANCER RESEARCH	7701 BURHOLME AVENUE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	1	4/28/2008	NEW	$323,233
														Subtotal = $323,233

Grand Total All Awards = $867,870

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REGULATION OF ONCOGENE-INDUCED SENESCENCE BY WNT-SIGNALING

Award Number: R01CA129334

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2008

PERIOD OF PERFORMANCE END DATE: 02/29/2012

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