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Role of ETS factors in specifying prostate luminal cell identity and androgen receptor dependence

Award Number: R01CA193837
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2015
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Role of ETS factors in specifying prostate luminal cell identity and androgen receptor dependence - ABSTRACT ETS family protein alterations (primarily ERG translocations) are present in >50% of human prostate cancers in Western men. We were the first to develop a robust GEM model of ERG-driven prostate cancer, revealing enhanced luminal differentiation and an expanded androgen receptor (AR) cistrome in tumors, suggesting a novel mechanism for ERG oncogenicity via chromatin programming (Chen, 2013). We and others subsequently established that ERG activates a luminal differentiation program in prostate organoids, human prostate cell lines and, by computational analysis of prostate cancer genomes, in clinical samples (Blee et al., 2018; Kron et al., 2017; Li et al., 2020b). Other ETS gain-of-function alterations e.g. ETV4 translocations (Li et al., 2020a) and ETS loss-of-function alterations e.g. ERF repressor mutations/deletions (Bose et al., 2017) also show this phenotype, as does FOXA1 (also amplified or mutated in prostate cancer) but with a contracted AR cistrome (Adams et al., 2019). Having demonstrated that luminal differentiation is a primary feature of multiple oncogenic ETS proteins (and FOXA1), our major goal during the next funding cycle is to understand how ERG activates this differentiation program and how this program results in an oncogenic phenotype. We will pursue three parallel lines of investigation. First, from our biochemical studies using purified full-length proteins and various DNA templates, we find that that ERG (and other ETS factors) cooperatively enhance AR DNA binding through allosteric effects via direct protein-protein interaction; biologically, this broadens the AR cistrome to include novel AR binding sites (Wasmuth et al., 2020). Aim 1 will expand this analysis to assess the role of FOXA1 on AR/ERG interactions. Second, we have built genetically defined prostate organoid models that recapitulate the luminal differentiation effect of ERG within a precisely defined time course. Using this system, we identified epigenetic changes that silence transcription of the basal epithelial master regulator p63, likely explaining the reduction in basal cells. Aim 2 will use lineage tracing, single cell analysis, and CRISPR screening to further elucidate how ERG expands the number of luminal cells and initiates oncogenic transformation. Third, we showed that another oncogenic ETS protein (ETV4) also drives luminal differentiation and is sufficient, alone, to initiate prostatic intraepithelial neoplasia (PIN). Remarkably, these luminal epithelial cells acquire exquisite dependence on AR for survival (in contrast to normal luminal epithelial cells) and consequently display enhanced sensitivity to androgen deprivation therapy (ADT). Aim 3 will explore mechanisms underlying this shift to cell-intrinsic AR dependence by examining changes in the AR cistrome and transcriptome following luminal-specific AR ablation (by genetic deletion) versus systemic androgen deprivation through surgical castration (impairs AR function in prostate stroma and epithelium). We will complement these experiments with single cell analysis of ETS-positive patient samples before and after ADT.


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 = $471,586 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	002	10	5/29/2025	NON-COMPETING CONTINUATION	$47,158
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	001	10	2/13/2025	NON-COMPETING CONTINUATION	$0
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	10	1/7/2025	NON-COMPETING CONTINUATION	$424,428
														Subtotal = $471,586

Issue Date FY: 2024 ( Subtotal = $448,006 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	9	1/9/2024	NON-COMPETING CONTINUATION	$424,428
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	001	9	4/18/2024	NON-COMPETING CONTINUATION	$23,578
														Subtotal = $448,006

Issue Date FY: 2023 ( Subtotal = $462,155 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	8	1/27/2023	NON-COMPETING CONTINUATION	$462,155
														Subtotal = $462,155

Issue Date FY: 2022 ( Subtotal = $462,155 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	7	2/10/2022	NON-COMPETING CONTINUATION	$424,428
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	001	7	6/8/2022	NON-COMPETING CONTINUATION	$37,727
														Subtotal = $462,155

Issue Date FY: 2021 ( Subtotal = $471,586 )
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	001	6	2/9/2021	COMPETING CONTINUATION	$471,586
2021	2019	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	002	5	5/27/2021	NON-COMPETING CONTINUATION	$0
2021	2019	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	5	2/1/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $471,586

Issue Date FY: 2019 ( Subtotal = $462,551 )
2019	2019	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	5	3/19/2019	NON-COMPETING CONTINUATION	$462,551
														Subtotal = $462,551

Issue Date FY: 2018 ( Subtotal = $468,128 )
2018	2018	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	4	3/5/2018	NON-COMPETING CONTINUATION	$421,315
2018	2018	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	001	4	5/23/2018	NON-COMPETING CONTINUATION	$46,813
														Subtotal = $468,128

Issue Date FY: 2017 ( Subtotal = $468,128 )
2017	2017	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	3	2/27/2017	NON-COMPETING CONTINUATION	$421,315
2017	2017	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	001	3	6/7/2017	NON-COMPETING CONTINUATION	$46,813
														Subtotal = $468,128

Issue Date FY: 2016 ( Subtotal = $468,128 )
2016	2016	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	2	3/14/2016	NON-COMPETING CONTINUATION	$468,128
														Subtotal = $468,128

Issue Date FY: 2015 ( Subtotal = $487,103 )
2015	2015	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	1	3/23/2015	NEW	$487,103
														Subtotal = $487,103

Grand Total All Awards = $4,669,526

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Role of ETS factors in specifying prostate luminal cell identity and androgen receptor dependence

Award Number: R01CA193837

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2015

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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