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Quantifying The Angiogenic Potential Of Triple Negative Breast Cancer Cells In A High Fidelity Patient-Derived, Tissue Engineered Biomimetic Platform
Ishani D. Premaratne, BA, Nicholas Williams, BA, Andrew J. Miller, BA, Daniel O. Lara, BA, Mariam Gadjiko, BA, Matthew A. Wright, BA, Arash Samadi, BA, Paula S. Ginter, MD, Kristy A. Brown, PhD, Jason A. Spector, MD.
Weill Cornell Medicine, New York, NY, USA.

PURPOSE: The interaction between breast cancer (BC) cells and key cells in their microenvironment has not been well studied in 3D models that accurately recapitulate the tumor microenvironment. We have engineered a revolutionary 3D ex vivo culture system to address this gap. Herein, we use this platform to study the interaction of HS-578T triple negative BC cells and Human Umbilical Vein Endothelial Cells (HUVECs), which are crucial to the process of angiogenesis and tumor metastasis.
METHODS: Patient-derived breast tissue was processed to isolate adipocytes, stromal cells, and breast organoids. These were suspended within a 0.3% Type I collagen scaffold. Collectively, these comprise the biomimetic platform. Next, 5k fluorescently tagged HS578T BC cells within 1 uL collagen were plated (hereafter referred to as "cancer button") at the center of each well. The buttons were covered either by a layer of Type I collagen ("collagen only") or collagen plus patient-derived breast tissue cells (Biomimetic Platform "BM"). In both groups, a monolayer of HUVECs was plated on top. Wells were also made in the same fashion but without "buttons" (HUVEC monolayer alone). Each well was imaged on days 0, 4, and 7 with confocal microscopy and HUVEC migration was analyzed using Imaris™. Linear mixed-effects models were used to estimate vertical changes of HUVEC cell position over time.
RESULTS: HUVECs migrated downward towards cancer cell buttons by an average of 27.01 microns (95% CI: -27.9, -26.2) after 4 days in collagen alone. They further migrated by an average of 9.7 microns (95% CI: -11.6, -7.5) per day from days 4 to 7. In the biomimetic platform (BM) group, HUVECs migrated downward by an average of 26.74 microns (95% CI: -17.5, -15.8) from days 0 to 4, and by 30.49 microns (95% CI: -33.1, -27.8) from days 4 to 7 (Figure 1A and 1B). The overall HUVEC distance migrated toward the cancer cell buttons over 7 days was significantly greater in BM groups compared to collagen only (p = 0.02) (Figure 2). In comparison, there was almost no HUVEC migration over 7 days in groups where a HUVEC monolayer was plated without a cancer button.
CONCLUSION: Migration of HUVECs toward breast cancer cell buttons can be measured in a quantitative and reliable fashion within standardized 3D tissue-engineered constructs that mimic the breast tumor microenvironment. These data indicate that accurate recapitulation of the tumor microenvironment is crucial for revealing the "true" influence of cancer cells within in vitro models, as evidenced by differential invasiveness of HUVECs in collagen alone vs BM. We envision translation of this in vitro system so that it may be used in a patient-specific fashion (patient tissue + patient tumor) to provide quantitative measures of the angiogenic potential of individual patient tumors.


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