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Functions of the LKB1 tumor suppressor in control in metabolism and epigenetics

Award Number: R01CA215498
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Functions of the LKB1 tumor suppressor in control in metabolism and epigenetics - Intermediates generated in cell metabolism also serve as substrates for covalent modification of chromatin, enabling the potential coupling of metabolic states and epigenetic control. This interplay between metabolic control and epigenetic reprogramming has been recently been proposed as a potential mechanism for regulation of stem cell differentiation and for pathologic processes such as cancer. We identify such a network as a major mediator of cell transformation downstream of the LKB1, an important tumour suppressor that is mutationally inactivated in many cancers (e.g. lung, pancreas). LKB1 encodes a serine-threonine kinase that integrates nutrient availability, metabolism and growth, although the mechanisms for LKB1-dependent tumour suppression remain elusive. By developing primary epithelial cell models and employing transcriptional, proteomics, and metabolic analyses, we find that oncogenic cooperation between LKB1 loss and KRAS activation, alterations commonly coinciding in human cancer, is fueled by pronounced rewiring of nutrient utilization. In particular, we demonstrate that LKB1 inactivation potentiates glycolysis while also channeling glycolytic intermediates to the serine-glycine-one carbon network coupled to generation of the methyl donor S-adenosylmethionine (SAM). In concert, DNA methyltransferases (DNMT1 and DNMT3A) are upregulated, leading to global elevation in genomic 5- methylcytosine levels. Correspondingly, LKB1 deficiency renders cells independent of exogenous serine for growth, but highly sensitive to inhibition of serine biosynthesis and DNA methylation in vitro and in vivo. Thus, we define a hypermetabolic state resulting from loss of LKB1 that links rewiring of glucose metabolism and chromatin regulation. This state both potentiates and is critically required for the tumorigenic program of LKB1- mutant cells, suggesting novel points of therapeutic intervention in defined patient subsets. Here, we will build on these exciting findings, with the goals of defining how this enhanced DNA methylation contributes to the tumor phenotypes, deciphering the signaling and transcriptional pathways by which LKB1 loss activates to SGOC network, and further establishing the therapeutic potential of targeting this pathway in relevant in vivo preclinical models.


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: 2024 ( Subtotal = $0 )
2024	2022	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	000	5	5/10/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $587,087 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	001	5	1/27/2022	SUPPLEMENT FOR EXPANSION	$106,959
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	002	5	7/14/2022	SUPPLEMENT FOR EXPANSION	$9,507
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	003	5	7/18/2022	NON-COMPETING CONTINUATION	$38,418
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	000	5	1/26/2022	NON-COMPETING CONTINUATION	$432,203
														Subtotal = $587,087

Issue Date FY: 2021 ( Subtotal = $599,069 )
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	000	4	2/1/2021	NON-COMPETING CONTINUATION	$599,069
														Subtotal = $599,069

Issue Date FY: 2020 ( Subtotal = $543,177 )
2020	2020	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	001	3	5/21/2020	SUPPLEMENT FOR EXPANSION	$62,951
2020	2020	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	000	3	1/8/2020	NON-COMPETING CONTINUATION	$480,226
2020	2020	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	002	3	6/2/2020	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $543,177

Issue Date FY: 2019 ( Subtotal = $465,818 )
2019	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	000	2	1/14/2019	NON-COMPETING CONTINUATION	$465,818
														Subtotal = $465,818

Issue Date FY: 2018 ( Subtotal = $480,226 )
2018	2018	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	000	1	12/28/2017	NEW	$480,226
														Subtotal = $480,226

Grand Total All Awards = $2,675,377

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Functions of the LKB1 tumor suppressor in control in metabolism and epigenetics

Award Number: R01CA215498

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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