Wong, C.-W.C.-W.WongHan, H.-W.H.-W.HanYU-WEN TIENSHAN-HUI HSU2020-02-202020-02-2020190142-9612https://www.scopus.com/inward/record.uri?eid=2-s2.0-85066053691&doi=10.1016%2fj.biomaterials.2019.05.013&partnerID=40&md5=8930ecb877c2d6de6c82a4c392ad7058https://scholars.lib.ntu.edu.tw/handle/123456789/461820Pancreatic stromal cells especially pancreatic stellate cells (PSCs) play a critical role in the progression of human pancreatic ductal adenocarcinoma (PDAC). However, the exact interaction between cancer cells and PSCs remains to be elucidated in order to develop more effective therapeutic approaches to treat PDAC. The microenvironment of PDAC shows higher hyaluronan (HA) levels, which is associated with poor prognosis of PDAC patients. In the current study, an efficient three-dimensional tumor spheroid model for PDAC was established. The pancreatic cancer cells and PSCs were co-cultured on hyaluronan grafted chitosan (CS-HA) coated plates to generate 3D tumor-like co-spheroids. The pancreatic cancer cells and PSCs (1:9 ratio) co-cultured on CS-HA coated plates were assembled into tumor-like co-spheroids with 3D core-shell structure in 48 h. These spheroids displayed potent in vitro tumorigenicity such as up-regulated expression of stemness and migration markers. The migration rate of cancer cells in spheroids (from 1:9 cell ratio) was much faster (3.2-fold) than that of cancer cells alone. Meanwhile, this unique co-spheroidal cancer cell structure with the outer wrap of PSCs contributed to the chemo-resistance of pancreatic cancer cells to gemcitabine as well as sensitivity to the combined gemcitabine and Abraxane treatment in vitro. The metastatic nature of the spheroids was confirmed by the zebrafish xenograft model in vivo. The compact and dynamic pancreatic cancer-PSC co-spheroids generated by the unique 3D co-culture platform on CS-HA biomaterials can mimic the PSC-constituting microenvironment of PDAC and demonstrate the chemo-resistant, invasive, and metastatic phenotypes. They have potential applications in personalized and high-throughput drug screening. ? 2019 Elsevier Ltd[SDGs]SDG3Chitosan; Cytology; Diagnosis; Diseases; Hyaluronic acid; Plates (structural components); Tumors; 3D spheroids; Core shell structure; Ductal adenocarcinomas; High throughput; Metastatic; Microenvironments; Pancreatic cancers; Stellate cells; Cells; biomaterial; chitosan; gemcitabine; hyaluronic acid; paclitaxel; biomaterial; chitosan; polyvinyl alcohol; adult; animal experiment; animal model; Article; cancer resistance; carcinogenicity; cell interaction; cell invasion; cell migration; cell structure; coculture; concentration (parameter); controlled study; drug screening; embryo; high throughput screening; human; human cell; in vitro study; metastasis; nonhuman; pancreas adenocarcinoma; pancreatic cancer cell line; pancreatic stellate cell; phenotype; priority journal; protein expression; reverse transcription polymerase chain reaction; tumor microenvironment; tumor spheroid; tumor xenograft; upregulation; zebra fish; adenocarcinoma; animal; cancer transplantation; cell motion; chemistry; confocal microscopy; gene expression profiling; multicellular spheroid; pancreas carcinoma; pancreas tumor; pathology; preclinical study; stroma cell; tumor cell line; tumor microenvironment; Adenocarcinoma; Animals; Biocompatible Materials; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Movement; Chitosan; Coculture Techniques; Drug Evaluation, Preclinical; Gene Expression Profiling; Humans; Microscopy, Confocal; Neoplasm Metastasis; Neoplasm Transplantation; Pancreatic Neoplasms; Pancreatic Stellate Cells; Phenotype; Polyvinyl Alcohol; Spheroids, Cellular; Stromal Cells; Tumor Microenvironment; Up-Regulation; Zebrafishjournal article10.1016/j.biomaterials.2019.05.013311326442-s2.0-85066053691