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A Patient-Specific Biomimetic Breast Platform Reveals Microenvironment-Driven Long-Distance Tumor Cell Migration
Matthew W. Liao
*, Samuel Medina, Olivia H. Carrafiell, Terrence C. Green, Xue Dong, Jason A. Spector
Weill Cornell Medicine, New York, NY
BACKGROUND: Engineering a more accurate
in vitro breast cancer model can improve understanding of tumor invasion in the native breast microenvironment. Our lab developed a 3D biomimetic platform incorporating patient-derived breast tissue. In these biomimetic (cell-containing) constructs, we now investigate proliferation and migration of triple-negative MDA-MB-231 (231) and estrogen receptor-positive MCF-7 tumor cells.
METHODS: Breast tissue from non-oncologic patients was processed to isolate adipocytes, stromal vascular fraction, and ductal organoids. Tri-layer 3D constructs (~50 µL) were created in 96-well plates: 1) base layer of 60,000 RFP-tagged 231 or MCF-7 cells, 2) middle layer of either breast tissue components suspended in 0.3% collagen ("Biomimetic) or 0.3% collagen alone ("Collagen"), and 3) top layer of 28,300 endothelial cells. Constructs were cultured and imaged on Days 1 and 4; counts were normalized (Day 4/Day 1). Vertical migration was asssessed using an Imaris algorithm reconstructing a regression plane, to define migratory cells as ±1 SD from the tumor layer mean z-position, long-distance migratory cells as >100 µm above this plane, and migration distance.
RESULTS: On Day 4, normalized cell counts were similar between Collagen and Biomimetic constructs for both 231 and MCF-7, with no difference in overall migratory fraction. However, in the Biomimetic constructs, 231 cells exhibited greater migration distance (
p<0.01) and a higher proportion of long-distance migratory cells (>100 µm) (
p<0.05). MCF-7 similarly showed increased migration distance (
p<0.05).
CONCLUSION: Incorporating patient-derived breast components significantly alters tumor cell migration. Despite similar proliferation and migratory fraction, biomimetic matrices increased long-distance migration for both 231 and MCF-7 cells, suggesting microenvironmental components support tumor invasion and may reveal invasive phenotypes not seen in simpler models. These data highlight the importance of incorporating biomimetic elements into 3D platforms to better model breast cancer invasion.
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