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Dissecting and targeting lysosomal signaling in kidney tumorigenesis

Award Number: R01CA260205
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/21/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Dissecting and targeting lysosomal signaling in kidney tumorigenesis - The lysosome, the main hub for cellular degradation and recycling processes, is emerging as a crucial signaling platform that controls cell metabolism. It is now clear that lysosomal signaling plays an important role in a variety of cancers. The Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is both a substrate and a regulator of the mTORC1 lysosomal kinase complex, which drives growth and whose hyperactivation is broadly associated with cancer. Overexpression or constitutive activation of TFEB results in kidney cancer in two distinct disease entities: MiT-TFE Renal Cell Carcinoma (RCC) and Birt- Hogg-Dube' (BHD) syndrome, an inherited disease caused by mutations of folliculin (FLCN), a crucial regulator of TFEB activity. The goal of this proposal is to elucidate the mechanisms underlying TFEB-mediated kidney tumorigenesis. Emerging evidence suggest that such mechanisms may be involved in other disorders associated to kidney cancer, such Tuberous Sclerosis. Using sophisticated kidney-specific mouse transgenic models and CRE-fluorescent reporters, we will perform metabolic, biochemical, cell biology, omic and tumorigenesis assays both in vivo and in renal cultured cells with the aim of identifying the metabolic and signaling programs that underlie BHD and MiT-RCC tumorigenesis. In particular, these studies will allow us to dissect TFEB-regulated pathways that drive kidney tumorigenesis in both an mTOR- dependent and independent manner. To dissect these oncogenic programs in mechanistic depth, we will perform a detailed molecular characterization of FLCN- and mTORC1- dependent TFEB phosphorylation, coupled with candidate-based and high throughput genetic screens for novel TFEB regulators. Together, these studies will shed light on the pathogenesis of kidney tumors, and point the way toward new targets and therapeutic strategies.


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 = $489,289 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Biology Research	000	4	2/28/2025	NON-COMPETING CONTINUATION	$489,289
														Subtotal = $489,289

Issue Date FY: 2024 ( Subtotal = $516,093 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Biology Research	000	3	2/20/2024	NON-COMPETING CONTINUATION	$488,930
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Biology Research	001	3	4/16/2024	NON-COMPETING CONTINUATION	$27,163
														Subtotal = $516,093

Issue Date FY: 2023 ( Subtotal = $532,176 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Biology Research	000	2	3/21/2023	NON-COMPETING CONTINUATION	$532,176
														Subtotal = $532,176

Issue Date FY: 2022 ( Subtotal = $552,374 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Biology Research	000	1	3/21/2022	NEW	$552,374
														Subtotal = $552,374

Grand Total All Awards = $2,089,932

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Dissecting and targeting lysosomal signaling in kidney tumorigenesis

Award Number: R01CA260205

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/21/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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