Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology

被引:81
作者
de la Pena, David Osuna [1 ,2 ,16 ]
Trabulo, Sara Maria David [1 ]
Collin, Estelle [2 ]
Liu, Ying [1 ,2 ]
Sharma, Shreya [1 ,17 ]
Tatari, Marianthi [1 ]
Behrens, Diana [3 ]
Erkan, Mert [4 ,5 ]
Lawlor, Rita T. [6 ,7 ]
Scarpa, Aldo [6 ,7 ]
Heeschen, Christopher [8 ,9 ]
Mata, Alvaro [2 ,10 ,11 ,12 ]
Loessner, Daniela [1 ,13 ,14 ,15 ]
机构
[1] Queen Mary Univ London, Barts Canc Inst, London, England
[2] Queen Mary Univ London, Inst Bioengn, London, England
[3] EPO Expt Pharmacol & Oncol GmbH, Berlin, Germany
[4] Koc Univ, Dept Surg, Sch Med, Istanbul, Turkey
[5] Koc Univ, Translat Res Ctr KUTTAM, Istanbul, Turkey
[6] Univ Verona, Dept Diagnost & Publ Hlth, Sect Pathol, Verona, Italy
[7] Univ Verona, Appl Res Canc Ctr, ARC Net, Verona, Italy
[8] Shanghai Jiao Tong Univ, Ctr Single Cell Omics, Sch Med, Shanghai, Peoples R China
[9] FPO IRCCS, Candiolo Canc Inst, Lab Pancreat Canc Heterogene, Turin, Italy
[10] Univ Nottingham, Sch Pharm, Nottingham, England
[11] Univ Nottingham, Dept Chem & Environm Engn, Nottingham, England
[12] Univ Nottingham, Biodiscovery Inst, Nottingham, England
[13] Monash Univ, Fac Engn, Dept Chem Engn, Melbourne, Vic, Australia
[14] Monash Univ, Fac Engn, Dept Mat Sci & Engn, Melbourne, Vic, Australia
[15] Monash Univ, Fac Med Nursing & Hlth Sci, Dept Anat & Dev Biol, Melbourne, Vic, Australia
[16] UCL, UCL Resp, Lungs Living Res Ctr, London, England
[17] Univ London, London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England
基金
欧洲研究理事会; 英国医学研究理事会; 英国生物技术与生命科学研究理事会; 英国惠康基金;
关键词
STEM-CELL; STELLATE CELLS; BIOMATERIALS; VITRO; EXPRESSION; PHENOTYPES; HYDROGELS; PLATFORM; COLLAGEN; PROMOTE;
D O I
10.1038/s41467-021-25921-9
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Personalized cancer medicine currently lacks custom platforms that mimic the microenvironment of human tissues. Here, the authors show how self-assembled patient-derived models of pancreatic cancer recapitulate key biological features of the original tumours such as matrix composition and stemness. Patient-derived in vivo models of human cancer have become a reality, yet their turnaround time is inadequate for clinical applications. Therefore, tailored ex vivo models that faithfully recapitulate in vivo tumour biology are urgently needed. These may especially benefit the management of pancreatic ductal adenocarcinoma (PDAC), where therapy failure has been ascribed to its high cancer stem cell (CSC) content and high density of stromal cells and extracellular matrix (ECM). To date, these features are only partially reproduced ex vivo using organoid and sphere cultures. We have now developed a more comprehensive and highly tuneable ex vivo model of PDAC based on the 3D co-assembly of peptide amphiphiles (PAs) with custom ECM components (PA-ECM). These cultures maintain patient-specific transcriptional profiles and exhibit CSC functionality, including strong in vivo tumourigenicity. User-defined modification of the system enables control over niche-dependent phenotypes such as epithelial-to-mesenchymal transition and matrix deposition. Indeed, proteomic analysis of these cultures reveals improved matrisome recapitulation compared to organoids. Most importantly, patient-specific in vivo drug responses are better reproduced in self-assembled cultures than in other models. These findings support the use of tuneable self-assembling platforms in cancer research and pave the way for future precision medicine approaches.
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页数:15
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