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Biomaterial substrate-derived compact cellular spheroids mimicking the behavior of pancreatic cancer and microenvironment
Chui-Wei Wonga, Hao-Wei Hana, Yu-Wen Tienb,∗∗, Shan-hui Hsua,c,d,∗ a Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan
b Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
c Research and Development Center for Medical Devices, National Taiwan University, Taipei, Taiwan
d Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan
Human pancreatic ductal adenocarcinoma (PDAC)
Pancreatic stellate cells (PSC)
Pancreatic 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 re-mains to be elucidated in order to develop more eﬀective therapeutic approaches to treat PDAC. The micro-environment 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 gem-citabine 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.