A 3D Fibrous Scaffold Inducing Tumoroids: A Platform for Anticancer Drug Development

Abstract

The development of a suitable three dimensional (3D) culture system for anticancer drug development remains an unmet need. Despite progress, a simple, rapid, scalable and inexpensive 3D-tumor model that recapitulates in vivo tumorigenesis is lacking. Herein, we report on the development and characterization of a 3D nanofibrous scaffold produced by electrospinning a mixture of poly(lactic-co-glycolic acid) (PLGA) and a block copolymer of polylactic acid (PLA) and mono-methoxypolyethylene glycol (mPEG) designated as 3P. Cancer cells cultured on the 3P scaffold formed tight irregular aggregates similar to in vivo tumors, referred to as tumoroids that depended on the topography and net charge of the scaffold. 3P scaffolds induced tumor cells to undergo the epithelial-to-mesenchymal transition (EMT) as demonstrated by up-regulation of vimentin and loss of E-cadherin expression. 3P tumoroids showed higher resistance to anticancer drugs than the same tumor cells grown as monolayers. Inhibition of ERK and PI3K signal pathways prevented EMT and reduced tumoroid formation, diameter and number. Fine needle aspirates, collected from tumor cells implanted in mice when cultured on 3P scaffolds formed tumoroids, but showed decreased sensitivity to anticancer drugs, compared to tumoroids formed by direct seeding. These results show that 3P scaffolds provide an excellent platform for producing tumoroids from tumor cell lines and from biopsies and that the platform can be used to culture patient biopsies, test for anticancer compounds and tailor a personalized cancer treatment.

The characteristics of Ishikawa endometrial cancer cells are modified by substrate topography with cell-like features and the polymer surface

“…The observations point to the substantial potential for these substrates to assist in studies using a cell-like topography aimed at, for instance, cell regulation of signaling molecules and molecular target drug specificity. 15,34 Because expression of signaling molecules is modified by the physical nature of a cell's environment, it is important that we reach a greater understanding of the effects of these interactions on the development of cancers. [35][36][37] In addition, we also noted, by using a similar topography with a different polymer, pST, that the topographical environment combines with polymer characteristics to have an important role in influencing the cell behavior through the physical characteristics.…”

Lung cancer cells survive epidermal growth factor receptor tyrosine kinase inhibitor exposure through upregulation of cholesterol synthesis

“…These results suggest that 20-60-day exposure to EGFR TKIs can confer a tolerance to the drugs when compared to unexposed cells. 35 We observed about a 2.5-fold greater lapatinib tolerance in FiSS-tumoroids derived from DT-H1650 tumor biopsies compared to parental-H1650 tumor biopsies ( Figure 1E). We have developed a FiSS culture environment that creates a more representative model of tumor growth and drug resistance, which resemble in vivo tumors.…”

“…[35][36][37] Tumor derived biopsy cultures: mice were injected subcutaneously on flanks with 3 million H1650 parental (right) and DT (left) cells. Cells were cultured in a humidified incubator at 37C in a 5% CO 2 (Carbon Dioxide) atmosphere.…”

“…This same trend was seen when H1299-parental and -DT cells were exposed to lapatinib ( Figure S1A). [35][36][37][38] We found that the FiSS platform promotes the growth of 3D tumor-like organoids (tumoroids) ( Figure 1C). These results suggest that 20-60-day exposure to EGFR TKIs can confer a tolerance to the drugs when compared to unexposed cells.…”

Biomaterials‐Based Approaches to Tumor Spheroid and Organoid Modeling

“…A more complex 3D nanofibrous scaffold was fabricated by electrospinning a mixture of PLGA, PLA, and monopolyethylene glycol (mPEG), that was designated as 3P. [140] Spheroid formation of MCF-7 breast cancer, PC3 prostate cancer, B16 melanoma, BG1 ovarian cancer, and LLC1 Lewis lung cancer cells was demonstrated and depended on the surface topography and charge of the 3P scaffolds. Compared to 2D culture of cells, spheroids in the 3P scaffolds showed upregulated levels of an EMT marker, vimentin, over time, and reduced E-cadherin expression.…”