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Mechanisms of Dynamic Transcriptional Reprogramming in Metastasis Stem Cells

Award Number: R37CA266185
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Mechanisms of Dynamic Transcriptional Reprogramming in Metastasis Stem Cells - Metastasis causes >90% of cancer death. The persistence and lethality of metastasis is driven by cells capable of self-renewal, slow cell-cycling, tumor re-initiation, and therapy resistance, termed metastasis stem cells (MetSCs). Development of effective strategies for eliminating metastasis requires a better understanding of the mechanisms that MetSCs exploit for survival. We recently demonstrated that (1) disseminating colorectal cancers (CRC) undergo a dynamic phenotypic switch from an LGR5+ tumor-initiating cancer stem cell (CSC) state to a distinct LGR5lowL1CAM+ state required for metastasis. (2) This phenotypic plasticity of MetSCs is retained in ex vivo patient derived organoids, which can be used to dissect mechanisms of plasticity. (3) L1CAM+ MetSCs are functionally distinct from intestinal tumor-initiating LGR5+ CSCs: L1CAM is required for organoid formation, the regeneration of intestinal epithelium after colitis, and tumor formation after metastatic dissemination. But unlike LGR5, it is dispensable for epithelial homeostasis or intestinal tumor initiation. In contrast to tumor initiation, where homeostatic stem cells undergo oncogene-driven hyper proliferation in intact tissues, metastasis subverts a regenerative mechanism to survive and regrow outside an intact epithelial niche. (4) We have shown that the principal driver of L1CAM expression is loss of epithelial integrity itself, acting via loss of E-cadherin intercellular adherens junctions to transiently displace the transcriptional silencer REST/NSRF from chromatin in quiescent MetSCs, in turn derepressing expression of L1CAM and other genes required for tissue regeneration1. Proliferation, restoration of epithelial structures, and macrometastatic outgrowth, on the other hand, require high REST levels. Our evidence suggests that MetSCs cells are regenerative stem cells that emerge directly in response to loss of epithelial integrity to drive repair, a phenotype of physiological wound healing that is redeployed in MetSCs. In this proposal, we will define the molecular mechanism by which REST chromatin binding is dynamically regulated in MetSCs, and how this in turn enables cell fate plasticity from stemness to proliferation. Our preliminary data implicates the mRNA binding protein ZFP36L1/2 in REST- mediated metastatic plasticity. Project hypothesis: The ZFP36L1/2REST axis is a master regulator of cell fate plasticity in intestinal epithelial progenitors. Aim 1: Define the function of the ZFP36L1/2-REST axis in normal and neoplastic intestinal stem cell self-renewal, differentiation, and proliferation. Aim 2: Dissect the molecular mechanism of ZFP36L1/2-mediated cell fate plasticity. Aim 3: Determine the functional consequences of ZFP36L1/2-REST dynamic regulation in metastatic seeding and colonization. Results will define mechanisms of cancer progression and identify putative therapeutic targets to limit regenerative plasticity, with potential to impact clinical outcomes.


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: 2025 ( Subtotal = $659,887 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	002	4	5/6/2025	NON-COMPETING CONTINUATION	$0
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	4	1/17/2025	NON-COMPETING CONTINUATION	$593,898
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	001	4	5/1/2025	NON-COMPETING CONTINUATION	$0
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	004	4	6/17/2025	NON-COMPETING CONTINUATION	$65,989
2025	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	003	3	6/16/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $659,887

Issue Date FY: 2024 ( Subtotal = $715,830 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	3	1/8/2024	NON-COMPETING CONTINUATION	$364,399
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	002	3	8/14/2024	SUPPLEMENT FOR EXPANSION	$76,187
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$20,245
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	003	3	8/16/2024	SUPPLEMENT FOR EXPANSION	$254,999
														Subtotal = $715,830

Issue Date FY: 2023 ( Subtotal = $396,790 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	001	2	3/14/2023	NON-COMPETING CONTINUATION	$32,391
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	2	12/30/2022	NON-COMPETING CONTINUATION	$364,399
														Subtotal = $396,790

Issue Date FY: 2022 ( Subtotal = $404,888 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	1	2/21/2022	NEW	$404,888
														Subtotal = $404,888

Grand Total All Awards = $2,177,395

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Mechanisms of Dynamic Transcriptional Reprogramming in Metastasis Stem Cells

Award Number: R37CA266185

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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