Friday, April 26, 2024 4/26/2024

The Effect of Serine Source on Nucleotide Metabolism in Cancer: Manipulating Environmental Nutrient Availability to Impact Tumor Growth

Award Number: F31CA236036
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

Project Summary/Abstract In order to double all biomass components and support cell division, proliferating cancer cells utilize specialized metabolic programs that affect reliance on particular nutrients. Understanding how the availability of specific nutrients regulates these biosynthetic networks therefore has great potential for developing cancer treatment strategies. In particular, production of nucleotides is critical for proliferating cells, and nucleotide synthesis is the target of many chemotherapies used in the clinic. To gain insight into the metabolic liabilities of nucleotide production, we assessed how nutrient availability affects nucleotide levels in cancer cells. Strikingly, we found that availability of extracellular serine is necessary for the production of nucleotides to support proliferation, even in cancer cells with upregulated intracellular serine synthesis. Serine can provide carbon substrates for nucleotides, but why the source of serine is important for nucleotide production is unclear. In considering this question, we noted that serine synthesis has a high demand for the oxidized cofactor NAD+, whereas direct consumption of serine does not. Indeed, decreasing NAD+ availability prevents serine synthesis and kills cells in the absence of exogenous serine, while enhancing NAD+ regeneration restores nucleotide synthesis and proliferation when extracellular serine is not available. This suggests that cellular redox state can regulate serine synthesis and subsequent use for nucleotide production. Further, dietary interventions to decrease plasma levels of serine inhibit tumor growth in mouse models, suggesting that environmental serine availability may create targetable liabilities in cancer. The overall goal of this project is to determine the role of serine source in regulating nucleotide metabolism to impact cancer cell proliferation. To address this question, I propose to: 1) Define how cellular redox state regulates serine synthesis and nucleotide production in tumors 2) Assess how nucleobase salvage compensates for nucleotide synthesis to support proliferation under serine deprivation 3) Determine how serine availability affects response to chemotherapies that target nucleotide metabolism By addressing these aims, I will gain insight into how environmental nutrient availability regulates nucleotide production in proliferating cells. Importantly, this will inform new strategies to target nucleotide metabolism for cancer therapy. Work on this project will also benefit my training to become a successful independent researcher. During this time, I will continue to develop in my career by attending and presenting my work at seminars and conferences, publishing first author papers, and mentoring younger students. Ultimately, work on this study will train me in addressing the long-term research interests I will pursue in my career: how fundamental biochemical processes affect the biology of 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: 2023 ( Subtotal = $0 )
2023	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	001	2	1/19/2023	NON-COMPETING CONTINUATION	$0
2023	2019	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	000	1	1/19/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = -$24,559 )
2022	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	000	3	1/27/2022	NON-COMPETING CONTINUATION	-$24,559
														Subtotal = -$24,559

Issue Date FY: 2021 ( Subtotal = $24,559 )
2021	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	000	3	8/18/2021	NON-COMPETING CONTINUATION	$24,559
														Subtotal = $24,559

Issue Date FY: 2020 ( Subtotal = $45,520 )
2020	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	001	2	7/1/2020	NON-COMPETING CONTINUATION	$45,520
2020	2019	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	000	1	6/25/2020	NEW	$0
														Subtotal = $45,520

Issue Date FY: 2019 ( Subtotal = $45,016 )
2019	2019	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	000	1	6/27/2019	NEW	$45,016
2019	2019	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	001	1	6/27/2019	NEW	$0
														Subtotal = $45,016

Grand Total All Awards = $90,536

Top

All Categories

About

Search

Reports

Data Submission

Award Information

The Effect of Serine Source on Nucleotide Metabolism in Cancer: Manipulating Environmental Nutrient Availability to Impact Tumor Growth

Award Number: F31CA236036

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer