Abstract 635: Osteoclasts mediate chemotherapy resistance in a fully humanized microphysiologic system of prostate cancer bone metastases
Authors: Ding Adeline B. , Heninger Erika , Reese Shannon R. , Sanchez-de-Diego Cristina , Yada Ravi C. , Sethakorn Nan , Kerr Sheena C. , Hazelberg Xavier T. , Sharifi Marina N. , Beebe David J. , Lang Joshua M. 
Published: March 2024

Abstract
Bone metastases (BM) are the most common sites of metastases in prostate cancer, occurring in ~85% of patients. Overall survival of men with castrate resistant prostate cancer with BM is less than 24 months. Docetaxel is the most commonly used therapy for patients with prostate cancer, but the response rate is only 30-40% and median duration of response is less than 9 months. Non-tumor components of the Tumor Microenvironment (TME) have been proposed to mediate treatment resistance, but few pre-clinical models capture the complex physiology of the human bone TME. We report the development of a bone TME using a humanized microphysiologic system to address this need. The LumeNEXT platform is a microphysiologic system that allows the 3-dimensional (3D) reconstitution and integrated analysis of a bone-specific TME microenvironment with functional microvasculature that traverses the chip and can be used to mimic drug delivery in patients. Primary human osteoclasts (OC) were differentiated from patient peripheral blood monocytes. LNCaP prostate cancer spheroids were grown in hanging droplets. We performed co-culture of OCs with 3D LNCaP spheroids and evaluated the efficacy of docetaxel-induced tumor cell killing in the presence of bone cells. OCs and PC spheroids were seeded into LumeNEXT devices in a collagen-based matrix and treated with 20 nM Docetaxel or DMSO vehicle for 48 hours. Docetaxel response was assessed using confocal microscopy for single spheroid diameter and cytotoxicity was measured using fluorescent cell death markers. Docetaxel-mediated killing of tumor spheroids was found to be significantly attenuated in the presence of OCs. In LNCaP only conditions, average Docetaxel-mediated cell death was 68.82%, compared to 53.86% in the LNCaP and OC co-culture condition (p&lt;0.0001). Furthermore, Docetaxel treatment resulted in reduced tumor spheroid diameter compared to DMSO control when prostate cancer spheroids were cultured alone (p=0.0118). Additionally, the presence of OCs attenuated Docetaxel-induced morphological changes. Our data suggest that osteoclasts play a significant role in mediating chemotherapy response in prostate cancer. Future studies will examine transcriptional changes in prostate cancer cells that may be associated with Docetaxel resistance in the bone microenvironment and identify mechanisms of BM microenvironment-mediated drug resistance. Bioinformatic analysis of patient sequencing datasets is ongoing to identify osteoclast-associated signatures of treatment resistance.
Citation Format: Adeline B. Ding, Erika Heninger, Shannon R. Reese, Cristina Sanchez-de-Diego, Ravi C. Yada, Nan Sethakorn, Sheena C. Kerr, Xavier T. Hazelberg, Marina N. Sharifi, David J. Beebe, Joshua M. Lang. Osteoclasts mediate chemotherapy resistance in a fully humanized microphysiologic system of prostate cancer bone metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 635.