BME Seminar: Cynthia Miranti
Monday, October 16, 2023 - 12 p.m.
Cynthia Miranti
Professor and Interim Department Head, Cellular and Molecular Medicine
Chair, Cancer Biology GIDP
Co-Program Leader, Cancer Biology Research Program
Professor, BIO5 Institute
University of Arizona
"Using a Microfluidic-based Tissue Chip to Model the Tumor Microenvironment in Prostate Cancer"
Keating 103
Zoom link | Password: BearDown
Hosts: Dr. Mario Romero-Ortega and Dr. Shang Song
(Instructor permission required for enrolled students to attend via Zoom)
Persons with a disability may request a reasonable accommodation by contacting the Disability Resource Center at 621-3268 (V/TTY).
Abstract: Tahsin, Shekha4, Sane, Neha S1, Cernyar, Brent1, Jiang, Linan2, Szewczyk, Kailie2, Zohar, Yitshak2,5, Lee, Benjamin R3,5, and Miranti, Cindy K1,4,5
1Department of Cellular and Molecular Medicine, 2Department of Aerospace and Mechanical Engineering, 3Department of Urology,4Cancer Biology Graduate Interdisciplinary Program, 5University of Arizona Cancer Center, University of Arizona, Tucson, AZ
Background: The secretion of morphogenic factors from the stroma, whose production is dependent on stromal androgen receptor(AR) action, is crucial for maintaining glandular structure and homeostatic function of the prostate gland. However, the precise nature of the factors involved, their regulation, and how they impact homeostasis in the human prostate is not clear. We hypothesize that loss of stromal AR function as seen in prostate cancer progression and during androgen-deprivation therapy likely contribute to tumor progression through disruption of this homeostasis. It is important to understand these interactions in the human context to better aid inimproving patient outcomes.
Approach: Microfluidic-based technology was used to develop the first human Prostate-on-Chip (PoC) where human prostate fibroblasts are co-cultured with human prostate basal epithelial cells under microfluidic flow. Addition of androgen to the stromal cellsis sufficient to induce luminal cell differentiation on top of the neighboring basal cells – recapitulating the cellular architecture of thehuman gland. To study prostate cancer in this context, we replaced the normal epithelial cells with tumor cells to interrogate the tumor-stromal interactions; thus, generating a human Prostate Cancer-on-Chip model (PCoC). Cytokine arrays and RT-qPCR were used to identify androgen-induced stromal morphogens and tumor cytokines involved in tumor/stromal interactions. Molecular biology approaches were used to identify the mechanisms involved.
Results: Within the PCoC model, tumor cells invaded into the stroma and conversely stromal cells invaded into the tumors. This was accompanied by localized CAF conversion of the stroma. Strikingly, the level of AR expression in the stroma was also reduced, recapitulating the loss of stromal AR expression seen in patients. A cytokine array identified TNFα and TGFβ as tumor secreted factorsresponsible for suppressing stromal AR protein and mRNA expression. TNFα suppressed stromal AR expression in the absence ofCAF conversion via NF-κB binding to two regions of the AR promoter. On the other hand, p38-MAPK signaling suppressed basal levels of AR expression independent of TNFα. FGF10 and Wnt16, but not KGF, were identified as androgen-induced stromal secreted morphogens. Loss of stromal AR expression led to suppression of FGF10 and Wnt16, but not KGF expression. Wnt16 is important formaintaining basal epithelial survival, and its loss during oncogenesis could contribute to the characteristic loss of basal cells seen inprostate cancer.
Conclusions: We have developed the first human Prostate-on-Chip and Prostate Cancer-on-Chip models which recapitulate the biology of both the normal human prostate as well as prostate cancer stromal interactions. These models can be used to address a range of clinical problems in cancer development, drug response, and biomarker identification in the context of the tumor microenvironment. This model can easily be adapted for personalized medicine approaches.
Funding: NIH/NCI CA254200, CA023075
COI: The Authors have no conflict of interest to declare.