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Live-cell Activity Architecture in Cancer

Award Number: R35CA197622
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2015
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Live-cell Activity Architecture in Cancer - Project summary: Essential regulation of the cellular machinery is achieved by a network of highly dynamic signaling molecules, which, when dysregulated, allow cancer cells to misinterpret or ignore signals that normally tell cells to stop dividing or begin apoptosis, leading to uncontrolled tumor growth. For the last 18 years, my laboratory has been at the forefront of applying a native biochemistry approach to cell signaling and cancer research. We have developed enabling technologies, and established spatiotemporal regulation as a fundamental paradigm in cell signaling, and discovered that its alteration leads to uncontrolled cell growth. This NCI R35-supported research program seeks to establish a new conceptual framework to specifically understand the cellular organization of molecular activities. We hypothesize that cellular biochemical activities are spatially organized into an “activity architecture” and dysregulated driver molecules can re-organize and re-structure this activity architecture, leading to loss of control over cell growth, division and death. In the past 6 years, we published 51 peer-reviewed articles, and made significant advances in establishing this framework. We developed first-in-class technologies for imaging protein-protein interactions and enzymatic activities in living cells at molecular length-scales and first kinase biosensor that achieved high- resolution imaging in awake mice, which have provided evidence for the biochemical activity architecture across different scales. We also made a breakthrough discovery that a regulatory subunit of Protein Kinase A (PKA), RIα, undergoes liquid-liquid phase-separation (LLPS) to enable the dynamic buffering and spatial compartmentalization of a ubiquitous second messenger, cAMP, providing an answer to a long standing question. We further showed that the oncogenic fusion in fibrolamellar carcinoma (FLC) potently inhibits RIα LLPS and induces aberrant cAMP signaling, which leads to increased cell proliferation and cell transformation. We have also discovered novel regulation in the Ras/ERK pathway and developed a novel Ras biosensor. In the proposed research, we will have three focuses. First, we will develop innovative technologies including super-resolution activity imaging to illuminate the biochemical activity architecture across different scales. Secondly, we will elucidate how the disorganized cAMP-PKA activity architecture leads to tumorigenesis in FLC, and further discover novel, cancer-relevant biomolecular condensates. Thirdly, we will investigate the spatiotemporal regulation of ERK that is critical for its physiological functions and identify the vulnerable connections in the re-organized cancer-driving architecture in pancreatic cancer, which is a deadly cancer that is addicted to the Ras-ERK pathway. We will also facilitate the development of new therapeutics by developing novel assays for evaluating Ras inhibitors and measuring target engagement.


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: 2026 ( Subtotal = $948,000 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	12	8/10/2026	NON-COMPETING CONTINUATION	$948,000
														Subtotal = $948,000

Issue Date FY: 2025 ( Subtotal = $948,000 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	11	8/1/2025	NON-COMPETING CONTINUATION	$948,000
														Subtotal = $948,000

Issue Date FY: 2024 ( Subtotal = $900,601 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	10	7/25/2024	NON-COMPETING CONTINUATION	$900,601
														Subtotal = $900,601

Issue Date FY: 2023 ( Subtotal = $929,040 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	001	9	7/27/2023	NON-COMPETING CONTINUATION	$929,040
2023	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	7	5/19/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $929,040

Issue Date FY: 2022 ( Subtotal = $948,000 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	8	7/28/2022	COMPETING CONTINUATION	$948,000
														Subtotal = $948,000

Issue Date FY: 2021 ( Subtotal = $930,000 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	7	8/31/2021	NON-COMPETING CONTINUATION	$930,000
														Subtotal = $930,000

Issue Date FY: 2020 ( Subtotal = $930,000 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	6	7/17/2020	NON-COMPETING CONTINUATION	$930,000
														Subtotal = $930,000

Issue Date FY: 2019 ( Subtotal = $902,101 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	5	7/29/2019	NON-COMPETING CONTINUATION	$902,101
														Subtotal = $902,101

Issue Date FY: 2018 ( Subtotal = $930,000 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	4	7/12/2018	NON-COMPETING CONTINUATION	$930,000
														Subtotal = $930,000

Issue Date FY: 2017 ( Subtotal = $930,000 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	3	7/17/2017	NON-COMPETING CONTINUATION	$930,000
														Subtotal = $930,000

Issue Date FY: 2016 ( Subtotal = $930,000 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	2	7/20/2016	NON-COMPETING CONTINUATION	$930,000
														Subtotal = $930,000

Issue Date FY: 2015 ( Subtotal = $930,000 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	1	7/29/2015	NEW	$930,000
														Subtotal = $930,000

Grand Total All Awards = $11,155,742

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Live-cell Activity Architecture in Cancer

Award Number: R35CA197622

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2015

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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