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Eco-evolutionary drivers of clonal dynamics during UV-induced skin carcinogenesis (PQ3)

Award Number: R01CA258089
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Eco-evolutionary drivers of clonal dynamics during UV-induced skin carcinogenesis (PQ3) - ABSTRACT Cancers have readily-defined characteristics often referred to as “hallmarks”. Nevertheless, the question of how the sequence of cancer development progresses -- from normal tissue to carcinogen-damaged tissue to precancerous lesion and finally to malignant tumors – remains unanswered. Classically, these steps are attributed to the sequential acquisition of discrete genetic events such as driver mutations. However, in humans, the clonal dynamics governing cancer development happen over years, remain largely invisible even in model systems, and have been difficult to link to specific molecular changes. This rubric fails to account for clonal dynamics in the context of tissue architecture and fails to explain the consequences of large numbers of mutations present in normal tissue. Our long-term goal is to apply ecological and evolutionary principles to cancer initiation and development in order to test whether the hallmarks of cancer are acquired in three distinct phases each with distinct selective pressures and manifestations of cell competition and cooperation. Nowhere is this more accessible to investigation than in skin. For skin carcinomas, the most important carcinogen is ultraviolet radiation. Cutaneous squamous cell carcinoma (cuSCC) has the most tractable and clinically well-characterized progression sequence of any human cancer, from normal tissue, to a distinct precancerous lesion (the actinic keratosis), to invasive carcinoma. Therefore, it is ideal for establishing an eco- evolutionary paradigm of cancer initiation and development with respect to modelling clonal dynamics, genetic composition and the dynamics of molecular traits. Our central hypothesis is that cancer initiation and development occurs in three phases, each with specific and recognizable clonal dynamics. In the first phase, tissue disruption from UV exposure provides a permissive environment where extrinsically-driven mechanisms allow for some clones to experience unusually long runs of cell division and turnover. This greatly increases the variance among clone sizes with larger clones accumulating greater heritable variation. The second phase sees the emergence of intrinsic mechanisms where mutations that confer a competitive advantage allow for clonal selection with directed expansion of some clones at the expense of others. In the third phase, one or several clones escape local tissue control, acquire a distinct fitness function, and form tumors. Within the emerging tumor microenvironments, selection pressures will promote ecological and molecular diversification of the malignant clade (or clades). Our approach uses novel combinations of serial in-vivo quantitative imaging, mathematical modeling, and deep single-cell molecular interrogation to discern the ecological and molecular drivers of clonal dynamics, cell-to- cell competition and cooperation, and clonal evolution, producing a fundamentally unprecedented view of cancer initiation.


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 = $640,021 )
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	000	5	3/4/2025	NON-COMPETING CONTINUATION	$576,018
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	001	5	5/23/2025	NON-COMPETING CONTINUATION	$64,003
														Subtotal = $640,021

Issue Date FY: 2024 ( Subtotal = $608,020 )
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$32,002
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	000	4	3/6/2024	NON-COMPETING CONTINUATION	$576,018
														Subtotal = $608,020

Issue Date FY: 2023 ( Subtotal = $627,220 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	000	3	3/20/2023	NON-COMPETING CONTINUATION	$627,220
														Subtotal = $627,220

Issue Date FY: 2022 ( Subtotal = $627,218 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	000	2	4/1/2022	NON-COMPETING CONTINUATION	$627,218
														Subtotal = $627,218

Issue Date FY: 2021 ( Subtotal = $640,021 )
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	000	1	3/29/2021	NEW	$640,021
														Subtotal = $640,021

Grand Total All Awards = $3,142,500

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Eco-evolutionary drivers of clonal dynamics during UV-induced skin carcinogenesis (PQ3)

Award Number: R01CA258089

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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