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Bioengineered Prostate-on Chip: Mechanisms of Stromal Dysregulation in Prostate Cancer

Award Number: R01CA254200
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/07/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Bioengineered Prostate-on Chip: Mechanisms of Stromal Dysregulation in Prostate Cancer - ABSTRACT It is well accepted that intrinsic action of the androgen receptor (AR) within the prostate epithelium drives prostate cancer proliferation and survival. Less appreciated is the fact that AR is also expressed in the stroma surrounding the epithelium. Stromal-expressed AR acts extrinsically to maintain the differentiated striated basal and luminal epithelium of the normal gland. During prostate cancer development, AR expression in the stroma is lost. How AR is lost from the stroma and how its loss promotes prostate cancer development is unknown. Our objectives are to define the mechanism that leads to stromal-specific AR loss and determine how AR loss in the stroma, in conjunction with epithelial oncogenesis, promotes prostate cancer development Based on our preliminary data, we hypothesize that tumor-derived TNFα/TGFβ1 transcriptionally suppresses AR expression in the stroma, causing loss of FGF10 and Wnt16 secretion, which are required to maintain the stratified epithelium through induction of luminal cells and maintenance of basal cells, respectively. To test this, we developed the first human Prostate-on-Chip model by culturing basal epithelial cells next to prostate stromal cells within a microfluidic device. Within this model, we can fully recapitulate the stromal AR-dependent induction of luminal epithelial cell differentiation. Furthermore, co-culturing normal stroma with tumor cells within this model leads to the induction of CAF phenotypes and reduced stromal AR expression, mimicking the tumor/host interactions seen in vivo. Models that recapitulate human glandular organization and its dysregulation during disease development are critical for our mechanistic understanding of how stroma and oncogenic epithelial interactions drive tumor development. We will test our hypothesis in three aims: 1) Determine the mechanism by which stromal AR maintains prostate epithelial cell differentiation. Our working hypothesis is that stromal AR signaling induces secretion of stromal FGF10 and Wnt16, which are required for induction of luminal epithelial cells and maintenance of basal epithelial cells, respectively. 2) Determine the mechanism by which AR expression is lost in the tumor stroma. Our working hypothesis is that tumor-secreted factors, TNFα and TGFβ1, acting through NF-κB signaling, suppress transcription of the stromal AR gene independent of CAF conversion. 3) Determine the functional consequence of tumor-induced stromal AR loss on prostate epithelial differentiation in a new de novo in situ human prostate cancer model. Our working hypothesis is that tumor-induced stromal loss of AR- dependent induction of Wnt16 and FGF10, via TNFα/TGFβ1, co-operates with epithelial oncogenes to accelerate tumor development and induce loss of basal epithelial cells. The proposed studies will be the first to demonstrate how TNFα/TGFβ-mediated suppression of stromal AR expression leads to the loss of Wnt16 and FGF10 to promote prostate cancer development. These studies will also provide the framework for further development of the first human Prostate-on-Chip model, which recapitulates human prostate biology, for basic and translation cancer research.


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 = $472,861 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cancer Biology Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$47,286
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cancer Biology Research	000	5	3/11/2025	NON-COMPETING CONTINUATION	$425,575
														Subtotal = $472,861

Issue Date FY: 2024 ( Subtotal = $451,639 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cancer Biology Research	001	4	4/18/2024	NON-COMPETING CONTINUATION	$23,771
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cancer Biology Research	000	4	3/7/2024	NON-COMPETING CONTINUATION	$427,868
														Subtotal = $451,639

Issue Date FY: 2023 ( Subtotal = $468,397 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cancer Biology Research	000	3	3/31/2023	NON-COMPETING CONTINUATION	$468,397
														Subtotal = $468,397

Issue Date FY: 2022 ( Subtotal = $472,143 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cancer Biology Research	001	2	6/7/2022	NON-COMPETING CONTINUATION	$38,542
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cancer Biology Research	000	2	3/17/2022	NON-COMPETING CONTINUATION	$433,601
														Subtotal = $472,143

Issue Date FY: 2021 ( Subtotal = $484,200 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cancer Biology Research	000	1	4/7/2021	NEW	$484,200
														Subtotal = $484,200

Grand Total All Awards = $2,349,240

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Bioengineered Prostate-on Chip: Mechanisms of Stromal Dysregulation in Prostate Cancer

Award Number: R01CA254200

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/07/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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