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Engineering A Patient-Derived Biomimetic Breast Cancer Platform to More Accurately Interrogate the Response to Chemotherapy
Sophia Salingaros
*, Abby Chopoorian Fuchsman, Kate Manley, Tim Y. Li, Xue Dong, Jason A. Spector
Weill Cornell Medicine, New York, NY
BACKGROUND: Engineering a patient-specific breast cancer platform would greatly improve our understanding of disease progression and treatment, as cell behavior varies greatly among patients. We have developed a biomimetic patient tissue-derived 3D platform comprised of all cellular components found within the breast. Here, we interrogate breast cancer cell behavior within this unique biomimetic (BM) platform in response to doxorubicin treatment.
METHODS: Non-oncologic breast tissue was processed to isolate mature adipocytes, stromal vascular fraction, and ductal epithelial organoids. Tri-layer 3D constructs (50µl) were made in a 96-well plate: 1) base layer of 6x10
4 RFP-tagged triple negative breast cancer cells (TNBC), 2) middle layer with either breast-derived components suspended in 0.3% collagen ("BM") or 0.3% collagen alone ("Collagen"), and 3) top layer of 2.8x10
4 GFP-tagged human umbilical vascular endothelial cells (HUVEC). Constructs were treated with doxorubicin: 0µM (no treatment), 1µM, 10µM, and 100µM, and incubated under standard conditions. Confocal imaging was performed immediately before (pre-treatment) and 2 days after (post-treatment). An Imaris™ machine learning algorithm was built to measure vertical z-axis TNBC position, and a regression plane reconstructed in RStudio. Tumor cells that moved one standard deviation from this plane were considered "migrated".
RESULTS: Normalized post-treatment TNBC cell count trended higher in BM wells than Collagen wells in all conditions (p>0.05). The half maximal inhibitory concentration (IC50) was 3.43µM in Collagen and 5.11µM in BM constructs. A significantly greater percentage of TNBC were migratory in BM wells versus Collagen wells at 10µM (p=0.024) and 100µM (p=0.008) doxorubicin.
CONCLUSION: Attenuation of the inhibitory effects of doxorubicin within the BM milieu suggests that breast-derived cells may be sequestering/metabolizing the tumoricidal agent, providing a more faithful characterization of cancer behavior. This platform holds immense potential as a personalized breast cancer screening model.
