title: 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.
authors.affiliation: Department of Molecular Medicine, University of South Florida, Tampa, Florida, United States of America ; USF Nanomedicine Research Center, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.
authors.forename: Yvonne K
authors.initials: YK
authors.lastname: Girard
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wang
authors.forename: Sowndharya
authors.initials: S
authors.lastname: Ravi
authors.forename: Mark C
authors.initials: MC
authors.lastname: Howell
authors.forename: Jaya
authors.initials: J
authors.lastname: Mallela
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Alibrahim
authors.forename: Ryan
authors.initials: R
authors.lastname: Green
authors.forename: Gary
authors.initials: G
authors.lastname: Hellermann
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Mohapatra
authors.forename: Subhra
authors.initials: S
authors.lastname: Mohapatra
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011091:Polyesters; D011092:Polyethylene Glycols / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D055672:Static Electricity; D046509:Tissue Culture Techniques / Q000379:methods*; D054457:Tissue Scaffolds; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D015820:Cadherins; D048049:Extracellular Signal-Regulated MAP Kinases; D019344:Lactic Acid; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011091:Polyesters; D011092:Polyethylene Glycols; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D047428:Protein Kinase Inhibitors; D014746:Vimentin; C033616:poly(lactide); C028210:monomethoxypolyethylene glycol