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Metabolic Recycling and Compartmentalization in Tumor Progression

Award Number: K00CA234839
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2022

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Metabolic Recycling and Compartmentalization in Tumor Progression - PROJECT SUMMARY Cancer cells elevate nutrient catabolism, causing excess production and accumulation of metabolic waste, especially lactate and ammonia. Using stable isotope tracing and mass spectrometry, we discovered that breast cancer cells scavenged ammonia generated by amino acid catabolism as a re-purposed nitrogen source for biomass (Spinelli et al. Science, 2017). Ammonia recycling accelerated proliferation in 3D cell culture and in vivo mouse xenograft models. These studies lead to two follow-up questions that will be addressed in Specific Aim 1 (F99 phase) of this proposal. First (Aim 1A), what is the mechanism by which ammonia stimulates breast cancer proliferation? Preliminary data supports the hypothesis that subcellular compartmentalization of ammonia metabolism is required for its effect on proliferation rate. Using metabolic tracing and rapid immunoprecipiation, we tracked the localization of ammonia assimilation to the mitochondria and the subsequent efflux of metabolites to the cytosolic fraction, showing a role in ammonia-stimulated proliferation. Second (Aim 1B), what is the effect of this novel ammonia-recycling pathway on response to therapy? Preliminary data shows that ammonia assimilation circumvents the effect of glutaminase (GLS) inhibitors through replenishing glutamate levels via glutamate dehydrogenase (GDH). Our proposed studies will determine if GDH and GLS inhibition are synergistic in vivo and in primary breast cancer tumors to elucidate a mechanism by which breast cancer cells are resistant to GLS inhibition. Beyond ammonia, mitochondria promote tumor growth and proliferation through numerous metabolic pathways. However, the mechanisms by which nutrients traverse the inner mitochondrial membrane are little studied, particularly because 45% of the mitochondria nutrient transporter family is uncharacterized. Therefore, using my expertise in metabolite tracing and mass spectrometry in addition to new skills gained in genetic (CRISPR) screening and bioinformatics, the proposed studies (Aim 2, K00 phase) will systematically assess the role of mitochondrial nutrient transporters in tumor growth and survival. These data will be the first to globally evaluate the essentiality of metabolic compartmentalization in cancer cells harboring oncogenic drivers such as KRAS, IDH and PI3K mutations. Furthermore, this study will elucidate the function of uncharacterized mitochondrial nutrient transporters. In addition to the proposed studies, the fellowship training plan includes gaining experience with mentorship, taking courses on responsible conduct of research, team management, and budgeting, and attending scientific conferences such as the Tumor Metabolism Keystone meeting to develop a network of scientific collaborators. The proposed studies will occur at Harvard Medical School and The Broad Institute, which have environments with the equipment, technology, core facilities, potential for collaboration, and the resources for research and career development needed to complete the proposed training plan.


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 = -$59,261 )
2023	2022	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	5	11/9/2022	NON-COMPETING CONTINUATION	-$59,261
														Subtotal = -$59,261

Issue Date FY: 2022 ( Subtotal = $105,154 )
2022	2022	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Cause and Prevention Research	001	5	7/11/2022	NON-COMPETING CONTINUATION	$0
2022	2022	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	5	3/15/2022	NON-COMPETING CONTINUATION	$105,154
														Subtotal = $105,154

Issue Date FY: 2021 ( Subtotal = $100,343 )
2021	2021	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	4	2/18/2021	NON-COMPETING CONTINUATION	$100,343
														Subtotal = $100,343

Issue Date FY: 2020 ( Subtotal = $95,531 )
2020	2020	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	3	2/7/2020	NON-COMPETING CONTINUATION	$95,531
														Subtotal = $95,531

Issue Date FY: 2019 ( Subtotal = $92,664 )
2019	2019	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Cause and Prevention Research	001	2	3/4/2019	EXTENSION WITH OR WITHOUT FUNDS	$2,213
2019	2019	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Cause and Prevention Research	002	2	8/6/2019	EXTENSION WITH OR WITHOUT FUNDS	$14,634
2019	2019	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	2	2/22/2019	EXTENSION WITH OR WITHOUT FUNDS	$75,817
														Subtotal = $92,664

Grand Total All Awards = $334,431

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Metabolic Recycling and Compartmentalization in Tumor Progression

Award Number: K00CA234839

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2022

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