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Polyamine-stimulated stem cell recruitment in arsenic-induced skin cancer

Award Number: R01CA190952
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/07/2015
PERIOD OF PERFORMANCE END DATE: 06/30/2021

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Polyamine-stimulated stem cell recruitment in arsenic-induced skin cancer - ¿ DESCRIPTION (provided by applicant): Exposure to arsenic via the drinking water is a global (including in the US), major public health problem, causing neoplasias of the skin and to a lesser extent in other tissues. It is likely that wound-associated inflammation plays a role in arsenic-induced skin tumorigenesis, particularly since arsenic-induced keratoses and tumors tend to be located at sites of friction and trauma not receiving maximum sunlight exposure. However, the mechanisms contributing to arsenic-induced cancer are complex and elusive, largely due to the lack of predictive animal models. Arsenic is a transplacental carcinogen in humans that appears to target keratinocyte stem cells (KSC) leading to dysregulation of the normally tightly regulated process of stem cell self-renewal and differentiation. Because carcinogen target cells are thought to be long lived, slowly cycling KSCs found in the hair follicl bulge region, it is essential to understand pathways that regulate KSC recruitment in skin carcinogenesis. Compelling recent data from our lab show that elevated levels of polyamines stimulate the recruitment of bulge stem cells in quiescent skin. Polyamines are amino acid-derived polycations that are required for cellular proliferation and for a wide variety of physiological functions such as signal transduction, gene expression, and ion channel function. A hallmark of tumor promoting activity involves the induction of ornithine decarboxylase (ODC), the initial rate-limiting enzyme in polyamine biosynthesis. Use of transgenic mouse models has demonstrated that increased ODC activity is sufficient to promote tumor development following a single low dose exposure to a carcinogen. We show for the first time that only in utero exposure to low levels of arsenic in the drinking water causes skin tumors in adult K6/ODC transgenic progeny mice. The Toll-like receptors (TLRs) are important modulators of inflammation, and TLR4 and its downstream adaptor protein MyD88 are required for DMBA/TPA skin carcinogenesis. We show an enrichment of TLR4 expression in bulge stem cells in mouse telogen phase skin and that increased keratinocyte polyamine levels (a cell stressor) induce release of HMGB1, a ligand and potent activator of TLR4. If arsenic exposure leads to an aberrant accumulation of bulge stem cells, then we hypothesize that polyamine- induced HMGB1 release in the epidermis activates TLR4 signaling in bulge stem cells, resulting in their mobilization out of the bulge region, stimulation of inflammatory cytokines, and promotion of arsenic- initiated skin cancer. We propose Aim 1) to investigate the effect of polyamines on bulge stem cells in arsenic-induced skin tumorigenesis and in stimulating recruitment of bulge stem cells into arsenic-induced skin tumors using GFP transgenic reporter mice for permanent labeling and lineage tracking of bulge stem cells and their progeny; and Aim 2) to evaluate the contribution of TLR4 signaling in polyamine-promoted/arsenic- induced skin tumorigenesis and inflammation using mice deficient in TLR4 and with human keratinocytes transformed with arsenic and primary keratinocytes isolated from mice exposed in utero to arsenic.


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: 2022 ( Subtotal = $0 )
2022	2019	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Cause and Prevention Research	000	5	11/23/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $366,114 )
2019	2019	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Cause and Prevention Research	000	5	6/24/2019	NON-COMPETING CONTINUATION	$366,114
														Subtotal = $366,114

Issue Date FY: 2018 ( Subtotal = $377,438 )
2018	2018	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Cause and Prevention Research	000	4	6/4/2018	NON-COMPETING CONTINUATION	$377,438
														Subtotal = $377,438

Issue Date FY: 2017 ( Subtotal = $377,438 )
2017	2017	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Cause and Prevention Research	000	3	6/20/2017	NON-COMPETING CONTINUATION	$377,438
														Subtotal = $377,438

Issue Date FY: 2016 ( Subtotal = $377,438 )
2016	2016	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 LANCASTER AVENUE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Cause and Prevention Research	000	2	6/10/2016	NON-COMPETING CONTINUATION	$377,438
														Subtotal = $377,438

Issue Date FY: 2015 ( Subtotal = $370,301 )
2015	2015	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 LANCASTER AVENUE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Cause and Prevention Research	000	1	7/7/2015	NEW	$370,301
														Subtotal = $370,301

Grand Total All Awards = $1,868,729

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Polyamine-stimulated stem cell recruitment in arsenic-induced skin cancer

Award Number: R01CA190952

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/07/2015

PERIOD OF PERFORMANCE END DATE: 06/30/2021

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