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Roles for Intracellular pH Dynamics in Cancer

Award Number: R01CA197855
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2016
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Roles for Intracellular pH Dynamics in Cancer - Abstract Although cancers have a constitutively increased intracellular pH (pHi) that enables disease progression, the molecular mechanisms mediating pHi-dependent cancer cell behaviors are understudied and incompletely understood. During the funding period we bridged protein electrostatics and cell biology to identify molecular mechanisms for pHi regulating tumorigenesis and metabolic reprogramming, and for conferring cancer- promoting functions of somatic mutations encoding charge changes in proteins. Our competing renewal applies our expertise in new directions to address two gaps in our understanding of pHi dynamics and cancer. First is how pHi dynamics can directly regulate gene expression. Our previous work resolved how pHi dynamics can regulate protein-phospholipid and protein-protein binding; however, how pHi dynamics can regulate protein-DNA binding, despite nuclear and cytosolic pH being similar, remains unknown. In Aim 1 we test a new idea on pHi titration of a histidine in the DNA-binding domain of transcription factors that forms hydrogen bonds with nucleotides in conferring target gene selectivity. This idea is applicable to at least 65 transcription factors with a nucleotide-binding histidine. Focusing on three transcription factors from different families, FOXC2, SOX4 and MAX that have roles in cancers, we will test the hypothesis that dysregulated pHi dynamics in cancer cells contributes to transcription factor-DNA binding selectivity for enabling cancer cell behaviors. We will resolve pH regulated affinities of DNA binding domains to recognized DNA motifs, identify pH-dependent genome-wide binding preferences, and determine pH regulated transcription factor-DNA binding selectivity in cancer cells. Additionally, we apply our predictions on pHi regulated selectivity of transcription factor-DNA binding by testing targeting the nucleotide-binding histidine to reactivate a tumor suppressor pathway in cancer cells. A second gap in our understanding is the role of pHi dynamics and heterogeneity in tumorigenesis. Based on our preliminary data of intercellular pHi heterogeneity in clonal cancer cell spheroids and organoids of cancer cells from human biopsies, and established roles for pHi dynamics in epithelial plasticity, cell migratory capacity, and stem cell differentiation, in Aim 2 we will test the hypothesis that pHi heterogeneity distinguishes tumor cell phenotypic heterogeneity. We will determine whether pHi heterogeneity reflects distinct cell phenotypes and identities in spheroids of clonal colorectal cancer cells and organoids derived from biopsies of human colorectal tumors, by transcriptomics profiles generated by single cell RNA-seq and genetically changed pHi. To resolve pHi dynamics and heterogeneity during tumorigenesis we use a Drosophila line we generated expressing a genetically encoded pHi biosensor that allows longitudinal imaging of pHi dynamics in vivo, which cannot be achieved with mouse models. Significant outcomes of our studies include showing for the first time that pHi can regulate transcription factor-DNA binding selectivity, new insights on emergent tumor cell properties, and clinical promise for targeting cancer cell pHi for prognostic value and selective delivery of therapeutics.


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 = $403,750 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	001	8	5/22/2025	NON-COMPETING CONTINUATION	$40,375
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	000	8	3/3/2025	NON-COMPETING CONTINUATION	$363,375
														Subtotal = $403,750

Issue Date FY: 2024 ( Subtotal = $383,563 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	002	7	3/14/2024	NON-COMPETING CONTINUATION	$363,375
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	003	7	4/16/2024	NON-COMPETING CONTINUATION	$20,188
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	001	6	3/6/2024	COMPETING CONTINUATION	$15,189
2024	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	000	5	3/6/2024	SUPPLEMENT FOR EXPANSION	-$15,189
														Subtotal = $383,563

Issue Date FY: 2023 ( Subtotal = $403,750 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	003	6	3/29/2023	COMPETING CONTINUATION	$403,750
2023	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	002	5	3/21/2023	SUPPLEMENT FOR EXPANSION	$0
2023	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	5	3/21/2023	NON-COMPETING CONTINUATION	$0
2023	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	001	5	3/21/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $403,750

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	002	5	4/14/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	001	5	4/14/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	5	4/14/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $93,282 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	5	9/21/2021	SUPPLEMENT FOR EXPANSION	$93,282
														Subtotal = $93,282

Issue Date FY: 2020 ( Subtotal = $822,779 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	5	5/28/2020	NON-COMPETING CONTINUATION	$502,597
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	002	5	9/14/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	001	5	7/8/2020	SUPPLEMENT FOR EXPANSION	$320,182
														Subtotal = $822,779

Issue Date FY: 2019 ( Subtotal = $509,099 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	001	4	5/30/2019	NON-COMPETING CONTINUATION	$403,444
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	3	4/25/2019	SUPPLEMENT FOR EXPANSION	$21,602
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	002	4	6/10/2019	SUPPLEMENT FOR EXPANSION	$84,053
														Subtotal = $509,099

Issue Date FY: 2018 ( Subtotal = $415,921 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	000	3	7/12/2018	NON-COMPETING CONTINUATION	$415,921
														Subtotal = $415,921

Issue Date FY: 2017 ( Subtotal = $415,921 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	000	2	5/19/2017	NON-COMPETING CONTINUATION	$415,921
														Subtotal = $415,921

Issue Date FY: 2016 ( Subtotal = $389,407 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	1	5/19/2016	NEW	$389,407
														Subtotal = $389,407

Grand Total All Awards = $3,837,472

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Roles for Intracellular pH Dynamics in Cancer

Award Number: R01CA197855

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2016

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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