BIA-ALCL And Systemic ALCL Proliferate Differently In Response To Silicone Implant Shells Within A Three-dimensional Organotypic Model Of The Breast Microenvironment
Carly Askinas, B.S., Xue Dong, M.D., Ph.D., Sabrina Shih, B.A., Nick Vernice, A.B., Jason A. Spector, M.D..
Weill Cornell Medicine, New York, NY, USA.
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a T-cell-derived lymphoma associated with device-based breast reconstruction, with a reported incidence anywhere between 1/1,000 and 1/30,000. As of October 2021, 1158 BIA-ALCL cases were reported with 35 deaths worldwide and in nearly every case, patients had a textured device at some point in time. Despite the increasing awareness and the high correlation with textured implants, the etiopathogenesis of BIA-ALCL remains largely unknown. We have developed a tissue-engineered biomimetic platform composed of patient-derived breast tissue derivatives that mimics the breast microenvironment to interrogate the role of the silicone shell in altering the behavior of normal and malignant T cell lines.
AbbVie Biocell textured and smooth breast implant shells were shaped to line 96-well plates. Patient-derived breast tissue from mammaplasty procedures was digested into cellular components of adipocytes, stromal vascular fraction, and epithelial duct organoids. The breast tissue components were embedded in 0.3% type I collagen along with BIA-ALCL cell line IL89 and systemic ALCL cell line SUPM2 (200,000 cells/mL) and placed into 96-well plates with and without implant shell lining. Other experimental groups included IL89 and SUPM2 cultured within either a type I collagen ECM alone or low serum feeding media alone with or without implant shell lining. Low serum feeding media (0.5% BSA) was applied in all the groups to limit the additional effect of growth factors on cell proliferation. Imaging was performed every two days for ten days using confocal microscopy. Cell proliferation was quantified and analyzed using ImageJ and MetaMorph software.
IL89 cultured in low serum feeding media proliferated moderately over 10 days with no significant difference between groups. However, IL89 embedded in 3D-collagen appeared to have limited proliferation and even decreased over 10 days regardless of well lining. Notably, IL89 cultured within the biomimetic platform survived and even proliferated, of which cells exposed to this platform and a textured implant shell increased significantly (21.5%) when compared to those exposed to no implant shell (3.7%) (p<0.05). SUPM2 exposed to low serum media and no implant appeared to have an increased rate of proliferation (p>0.05). In collagen only, SUPM2 with all different implant shell linings stabilized or moderately proliferated with significant increases in textured and smooth groups when compared to no implant. In the biomimetic platform, SUPM2 had a higher rate of proliferation when compared to collagen only, which was not significant between groups.
When cultured in a 3D breast biomimetic platform, BIA-ALCL cells proliferate within a simulated breast microenvironment even without the addition of growth factors, while limited or decreased proliferation is seen when cultured in the same conditions without such cellular components. We have shown a difference in the cell proliferation trends that occur when different ALCL lines are cultured in 2-dimensions (media only) versus 3-dimensions (collagen embedded), emphasizing the physiologic relevance of our 3-dimensional model. These data demonstrate the importance of recapitulating the cellular microenvironment ex vivo to elicit pathologic in vivo cell behaviors that do not occur under standard culture conditions.
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