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

生物工程前列腺芯片：前列腺癌基质失调的机制

基本信息

批准号：
10593937
负责人：
Cynthia K Miranti
金额：
$ 46.84万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-07 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593937
关键词：
AR gene Acceleration Address Age Androgen Receptor Basal Cell Basic Cancer Research Biological Testing Biology Biomedical Engineering Cell Differentiation process Cell Line Cell Survival Cells Coculture Techniques Data Dependence Development Diagnosis Disease Epithelial Cells Epithelium FGF10 gene Fibroblasts Genetic Transcription Gland Human In Situ Individual MAP3K7 gene Maintenance Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Microfluidic Microchips Modeling NOTCH3 gene Oncogenes Oncogenic Oranges Patients Phenotype Physiological Proliferating Prostate Receptor Signaling Repression Signal Induction Signal Transduction Stratified Epithelium Stromal Cells Structure TNF gene Testing Tissues Transforming Growth Factor beta Tumor Cell Line Tumor-Derived cancer cell carcinogenesis gene repression human model in vivo man men morphogens neoplastic cell new technology overexpression preservation prostate cancer model receptor expression translational cancer research tumor tumorigenesis tumorigenic

项目摘要

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.

摘要