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Histone modifications regulating phenotype plasticity: Role of non-canonical Wnt signaling

Award Number: R00CA208012
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/05/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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Histone modifications regulating phenotype plasticity: Role of non-canonical Wnt signaling - Project Summary The goals of this Pathway to Independence Career Development proposal are to request support for training to develop expertise in cancer epigenetics while addressing the role of slow cycling cells and histone modifications in phenotype plasticity of highly resistant metastatic melanoma. K99/R00 support during this part of my career will be integral to my successful development as an independent cancer researcher. The training plan outlined in this proposal will take advantage of the extensive resources at The Wistar Institute, University of Pennsylvania as well as Temple University. My training will also be guided by senior personnel who have successfully mentored predoctoral, postdoctoral, and clinical fellows in academic careers. The scientific portion of this proposal focuses on experimentally determining the molecular mechanism underlying phenotype plasticity and therapy resistance of invasive melanoma and the role of epigenetic changes in phenotype plasticity and maintenance of slow cycling cells. The proposed studies are based on my previous findings that a subset of melanoma cells, which express Wnt5A and p21, survive multiple types of stress by entering a slow-cycling, senescent-like state, but still invade and retain the ability to form metastases. My preliminary data suggest SEDTB1 expression correlates with an invasive phenotype in our human melanoma cell lines and driving non-invasive melanoma cells to a more invasive phenotype, through over expression of Wnt5A, increases SETDB1 expression. Expression of SETDB1, a histone methyltransferase, has been implicated in the silencing of tumor suppressor p16. p16 is expressed in melanocytes and early stages of melanoma but is lost during melanoma progression and this correlates with p21 expression and a senescent-like response following stress. In melanoma, hypermethylation during tumor progression is observed, which may block the expression of multiple tumor suppressor genes, but the role of specific epigenetic changes in phenotype plasticity and drug resistance is still largely unknown. Therefore, in line with these data I will explore the following scientific aims: 1) to elucidate the mechanism by which Wnt5A and p21 promote the maintenance of slow cycling stem-like cells;; and 2) to determine if histone modifications induced by SETDB1 promote phenotype plasticity and invasion in melanoma cells. The completion of the scientific aims in this proposal will develop my research skills and knowledge in cancer epigenetics while delineating the mechanism by which highly invasive resistant cells evade stress to promote melanoma metastasis and therapy resistance.


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: 2024 ( Subtotal = -$1 )
2024	2021	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	000	5	2/9/2024	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2021 ( Subtotal = $249,000 )
2021	2021	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	000	5	8/9/2021	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2020 ( Subtotal = $249,001 )
2020	2020	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	001	4	8/26/2020	NON-COMPETING CONTINUATION	$246,478
2020	2019	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	000	3	1/19/2020	EXTENSION WITH OR WITHOUT FUNDS	$2,523
														Subtotal = $249,001

Issue Date FY: 2019 ( Subtotal = $249,000 )
2019	2019	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	000	3	9/6/2019	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $747,000

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Histone modifications regulating phenotype plasticity: Role of non-canonical Wnt signaling

Award Number: R00CA208012

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/05/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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