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Selection of oncogenic Ras mutations through tumor promotion mechanisms

Award Number: F31CA271737
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 10/31/2024

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Selection of oncogenic Ras mutations through tumor promotion mechanisms - Project Summary Recent investigations have revealed that oncogenic mutations are not sufficient for initial stages of tumorigenesis and that the microenvironment plays a significant role in promoting neoplastic growth of a tumor. This microenvironment surrounding a mutated cell can be influenced by many promotion processes, including environmental exposures, tissue damage, and chronic inflammation. This proposal aims to investigate the mechanisms by which promotion, or non-mutagenic processes, can influence the selection of mutant clones which eventually populate a tumor. This project will rely on theories from cancer genetics, tumor promotion, and evolutionary cancer biology in order to provide insight into the coordination between promotion and oncogenic mutations present in a cell. Through the use of a well-established model of chemical carcinogenesis, this project will address a fundamental question regarding the molecular consequences of tumor promotion. This carcinogenic regimen can produce both Hras mutant tumors and Kras mutant tumors, merely by adjusting the genetic background of the mouse. This provides the ideal tool for us to ask the question, what are the different promotion mechanisms which select for tumors with different mutations? To address this question, the proposed project aims to characterize promotion mechanisms on the backgrounds of the mice which are known to produce tumors with different mutations. The first aim will investigate how macrophage infiltration during promotion coordinates with oncogenic Hras signaling. This will be addressed by computationally identifying signaling axes between macrophages and epithelial cells from skin collected at different time points after application of a promoter. The second aim will define the active functional modules in the Kras-tumor-permissive skin, in response to a promoter. This will be achieved by constructing gene co-expression networks from single cell RNA sequencing of skin collected subsequent to promoter treatment in the skin. The proposed research will be completed by a graduate student with significant experience in both cancer biology and computational biology. It will be supervised by and conducted in the lab of Allan Balmain, an expert in the field of skin cancer genetics and tumor promotion. This training plan takes advantage of the highly collaborative and innovative research environment in the Helen Diller Family Comprehensive Cancer Center, which facilitates access to renowned scientific mentors and guidance in the proposed work. At the University of California, San Francisco (UCSF), the graduate program in Biomedical Sciences is regarded as one of the best due to its inclusion of professional development and training resources offered, which will support this highly motivated student to develop an independent research career. Completion of the proposed work will thus expand knowledge on a critical question in cancer biology and is enabled by an excellent institutional environment. Understanding how oncogenic mutations can coordinate with tumor promotion mechanisms in the mutant cell’s microenvironment will provide novel insights towards early detection and prevention strategies for cancer.


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 = -$2,352 )
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Research Manpower	001	2	9/24/2025	NON-COMPETING CONTINUATION	$0
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Research Manpower	000	2	3/31/2025	NON-COMPETING CONTINUATION	-$2,352
														Subtotal = -$2,352

Issue Date FY: 2024 ( Subtotal = $40,950 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Research Manpower	001	2	5/7/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Research Manpower	000	2	12/8/2023	NON-COMPETING CONTINUATION	$39,670
														Subtotal = $40,950

Issue Date FY: 2022 ( Subtotal = $38,728 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Research Manpower	001	1	9/1/2022	NEW	$0
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Research Manpower	000	1	9/1/2022	NEW	$38,728
														Subtotal = $38,728

Grand Total All Awards = $77,326

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Selection of oncogenic Ras mutations through tumor promotion mechanisms

Award Number: F31CA271737

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 10/31/2024

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