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Stem Cell Competition in Skin Homeostasis and Premalignancy

Award Number: F31AR085502
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/18/2025
PERIOD OF PERFORMANCE END DATE: 04/17/2027

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Stem Cell Competition in Skin Homeostasis and Premalignancy - Project Summary/Abstract Cell competition is a fitness-sensing mechanism where more-fit “winner” cells eliminate less-fit “loser” cells. First described to optimize overall tissue fitness, cell competition can also give rise to cells with enhanced fitness, such as those with oncogenic potential. These dual roles of cell competition may explain why oncogenic cells can initiate tumors (oncogenic winners/wild-type (WT) losers), but also why they often do not lead to overgrowth despite their accumulation in epithelial tissues (WT winners/oncogenic losers). However, it is unclear how losers are eliminated or restrained, nor how winners identify and eliminate losers. Insight into the competitive cell-cell interactions occurring during both homeostasis and premalignancy will thus fill a critical knowledge gap and address a pressing need for preventing oncogenesis at early stages. To address this hypothesis, I have preliminarily studied competitive interactions between a model for premalignancy and their WT neighbors in the embryonic mouse epidermis, which harbors epidermal stem cells (EpSCs) capable of acquiring oncogenic potential and is a well-characterized cell competition model. I observed that sparse, premalignant EpSCs ectopically expressing SOX2 are actively eliminated by WT neighbors and homeostasis is maintained. Interestingly, this loser status seems modulated by the degree of homo/heterotypic interactions (HHIs), or who their neighbors are. In fact, SOX2 EpSCs shed their loser status and initiate pathological overgrowth when SOX2 EpSC abundance in the tissue is increased. Armed with a premalignant model that can behave like a winner or loser depending on their cellular “neighborhood”, I propose to mechanistically dissect how these competitive statuses are assigned and further underlie homeostasis and premalignancy. Aim 1 will address how SOX2 and WT EpSC losers are eliminated. Building upon my preliminary data suggesting that intercellular adhesion is increased between SOX2 EpSCs in loser contexts, I will perform in vitro assays and in vivo lineage tracing to assess resulting differentiation and/or anoikis. Aim 2 will interrogate context- and contact-specific transcriptomic programs to uncover how SOX2 EpSCs eliminate WT neighbors and vice versa. Using a lab-verified, in vivo contact-based tagging and purification system coupled with single- cell RNA-sequencing, I will mechanistically decipher how winners identify and kill losers during both homeostasis and premalignancy. Completion of these aims will increase our understanding of the mechanisms underlying cellular fitness in cell competition; uncover the inherent, tissue-level dynamics used to maintain homeostasis in the face of premalignancy; characterize the very earliest stages of overgrowth initiation; and elucidate the “tipping point” between epithelial homeostasis and oncogenesis.


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: 2026 ( Subtotal = $50,114 )
2026	2026	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/27/2026	NON-COMPETING CONTINUATION	$50,114
														Subtotal = $50,114

Issue Date FY: 2025 ( Subtotal = $48,974 )
2025	2025	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	4/18/2025	NEW	$48,974
2025	2025	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	4/22/2025	NEW	$0
														Subtotal = $48,974

Grand Total All Awards = $99,088

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Stem Cell Competition in Skin Homeostasis and Premalignancy

Award Number: F31AR085502

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/18/2025

PERIOD OF PERFORMANCE END DATE: 04/17/2027

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