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Cancer Technologies

Cancer Technologies - Poster Session E

Poster S15 - Creating well-defined high-throughput breast cancer dormancy models with bioprinting for probing and targeting late recurrence

Saturday, October 26, 2024
10:00 AM - 11:00 AM EST
Location: Exhibit Hall E, F & G

Introduction:  Late recurrences, especially in estrogen receptor-positive breast cancer (ER+ BC), often occur in distant metastatic sites like the bone marrow (BM) and are hypothesized to be triggered by local microenvironment interactions that stimulate the growth of dormant disseminated tumor cells (DTCs). While progress has been made in understanding this complex process, challenges remain in the detection, prevention, and treatment of late recurrences, leading to low survival rates. To enable related studies, in vitro human 3D culture models of BC cell (BCC) dormancy have been developed. Yet, accessibility, throughput, and variability remain a challenge in broad use. Innovative technologies are needed to address these challenges and produce well-defined, accessible, high-throughput (HT) human models for mechanistic studies and identifying effective therapeutics. To address this need, our recent work established a tunable synthetic three-dimensional (3D) indirect co-culture system of ER+ BCCs with BM niche cells and identified the role of soluble secreted factors in the dormancy and re-activation of DTCs, benchmarked versus a preclinical animal model1. We now are translating this system to a HT human 3D co-culture model utilizing bioprinting. Specifically, we are using the Inventia RASTRUM for the rapid creation of multi-well plate co-cultures with different configurations and levels of control of cell-microenvironment interactions. We have successfully established innovative bioprinted co-culture systems with controlled complexity using the RASTRUM and made observations consistent with our manually-prepared ER+ BCC 3D co-culture model for the identification of pathways that regulate dormancy/activation and relevant drugs for targeting these pathways toward preventing late recurrence.

Materials and

Methods:  We have designed a dual and triple matrix-based 3D co-culture dormancy and reactivation model of ER+ breast cancer cells (T47D), where we used GFP transduced T47D for better monitoring the cell response over time with bone lining human osteoblast cells (hFOBs, BM niche cells). We characterized the GFP expression of BCCs over time (not shown here) and immunostaining with and without treatments.

Results, Conclusions, and Discussions: In this work, we have utilized a synthetic bioprinted hydrogel to mimic the microenvironment of late recurrence sites like BM. We reproduced our existing manually-prepared ER+ BCC 3D model to probe survival mechanisms, including autophagy. In mult-well plate bioprinted 3D co-culuctures, we observed that T47D enter a dormant phase with hFOBs, whereas T47D alone showed proliferation over time. A combination of specific antagonists regulated activation of dormant BCCs (Figure 1).

These results support the utility of bioprinting technology for the translation and creation of HT 3D co-cultures. With this approach, a HT model of breast cancer dormancy with increasing complexity was established and used to identify treatment strategies for modulating cancer cell dormancy/activation and preventing survival and re-activation of dormant BCCs toward preventing late cancer recurrence. These 3D co-culture systems printed with the Inventia RASTRUM are promising for future HT screening studies.

References: 1. Pradhan L., et al. Sci. Adv., 2023, 9, eade3186; 2. Sosa, M. S., et al., Nat. Rev. Cancer 2014, 14, 611; 3. Ghajar, C. M., et al., Nat. Rev. Cancer 2015, 4, 23; 4. Sawicki, L. A., et al., APL Bioeng. 2019, 3, 016101; 5. Marlow, R., et al., Cancer Res. 2013, 73, 6886.

Acknowledgements (Optional):  This work is collaborated with industrial partner Inventia Life Science with support from a grant from Delaware Bioscience Center for Advanced Technology (12A00448).