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Elucidating the mechanisms underlying cell cycle regulation of invasive behavior

Award Number: R01GM121597
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/13/2017
PERIOD OF PERFORMANCE END DATE: 12/31/2022

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Elucidating the mechanisms underlying cell cycle regulation of invasive behavior - Project Summary/Abstract Cell invasion through the basement membrane is a key mechanism underlying cell dispersal and organ formation during normal development, immune surveillance and is dysregulated during cancer metastasis. Yet due to difﬁculties of studying these dynamic behaviors in vivo, it is the least understood aspect of the metastatic cascade. My laboratory utilizes a powerful in vivo model to examine cell invasive behavior, by combining functional genomic and genetic tools with single-cell visual analyses. We examine anchor cell (AC) invasion into the vulval epithelium during C. elegans larval development. Data from our laboratory has shown a functional link between G1 phase cell cycle arrest and the acquisition of an invasive phenotype. Through high- throughput screens, we have identiﬁed that the activity of a single conserved NR2E1 class nuclear hormone receptor, the transcription factor, nhr-67 (TLX), is required to maintain the invasive AC in G1 cell cycle arrest. Loss of nhr-67 results in mitotic ACs that fail to invade. Strikingly, AC invasion can be rescued by preventing cell division through induction of G1 cell cycle arrest. Downstream of G1 arrest, chromatin modiﬁers, including the histone deacetylase, hda-1, are required for expression of pro-invasive genes, including matrix metalloproteinases (MMPs) and regulators of the F-actin cytoskeleton, leading to differentiation of the invasive phenotype. For this proposal we plan to elucidate how cell cycle arrest is functionally linked to invasion. In Aim 1, using molecular epistatic interaction experiments and inducible transgene expression, we will identify the upstream network of transcription factors that mediate NHR-67 activity. In Aim 2, we will generate CRISPR/Cas9-mediated conditional alleles of cell cycle control genes to determine how the AC maintains G1 arrest. In Aim 3, we will pair tissue-speciﬁc RNAi screening of chromatin modiﬁers with high resolution confocal and structured illumination (SIM) imaging of sub-nuclear organization, to understand the link between invasion and differentiation. The results of these aims will provide the ﬁrst mechanistic view of the transcriptional and epigenetic control of cell cycle arrest and invasive behavior. Thus, our proposed work has the potential to provide a mechanistic understanding of how cells acquire and maintain an invasive phenotype, a critical aspect of many developmental and genetic disorders.


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: 2023 ( Subtotal = -$51,270 )
2023	2021	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	5	8/14/2023	NON-COMPETING CONTINUATION	-$51,270
														Subtotal = -$51,270

Issue Date FY: 2021 ( Subtotal = $451,456 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	5	1/27/2021	NON-COMPETING CONTINUATION	$406,310
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	001	5	2/15/2021	NON-COMPETING CONTINUATION	$45,146
														Subtotal = $451,456

Issue Date FY: 2020 ( Subtotal = $435,991 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	4	1/6/2020	NON-COMPETING CONTINUATION	$356,156
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	001	4	3/17/2020	NON-COMPETING CONTINUATION	$39,573
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	002	4	6/26/2020	SUPPLEMENT FOR EXPANSION	$40,262
														Subtotal = $435,991

Issue Date FY: 2019 ( Subtotal = $407,372 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	001	3	8/1/2019	SUPPLEMENT FOR EXPANSION	$25,822
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	3	12/28/2018	NON-COMPETING CONTINUATION	$381,550
														Subtotal = $407,372

Issue Date FY: 2018 ( Subtotal = $429,132 )
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	003	2	8/15/2018	SUPPLEMENT FOR EXPANSION	$49,500
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	001	2	1/4/2018	SUPPLEMENT FOR EXPANSION	$49,376
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	002	2	5/21/2018	NON-COMPETING CONTINUATION	$33,027
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	2	12/28/2017	NON-COMPETING CONTINUATION	$297,229
														Subtotal = $429,132

Issue Date FY: 2017 ( Subtotal = $333,360 )
2017	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	1	1/13/2017	NEW	$333,360
														Subtotal = $333,360

Grand Total All Awards = $2,006,041

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Elucidating the mechanisms underlying cell cycle regulation of invasive behavior

Award Number: R01GM121597

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/13/2017

PERIOD OF PERFORMANCE END DATE: 12/31/2022

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