Bauer L. LeSavage, Daiyao Zhang, Carla Huerta-López, Aidan E. Gilchrist, Brad A. Krajina, Kasper Karlsson, Amber R. Smith, Kremena Karagyozova, Katarina C. Klett, Michelle S. Huang, Christopher Long, Gernot Kaber, Christopher M. Madl, Paul L. Bollyky, Christina Curtis, Calvin J. Kuo, Sarah C. Heilshorn
{"title":"工程基质揭示了源自患者的胰腺癌器官组织中由硬度介导的化疗抗性。","authors":"Bauer L. LeSavage, Daiyao Zhang, Carla Huerta-López, Aidan E. Gilchrist, Brad A. Krajina, Kasper Karlsson, Amber R. Smith, Kremena Karagyozova, Katarina C. Klett, Michelle S. Huang, Christopher Long, Gernot Kaber, Christopher M. Madl, Paul L. Bollyky, Christina Curtis, Calvin J. Kuo, Sarah C. Heilshorn","doi":"10.1038/s41563-024-01908-x","DOIUrl":null,"url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is characterized by its fibrotic and stiff extracellular matrix. However, how the altered cell/extracellular-matrix signalling contributes to the PDAC tumour phenotype has been difficult to dissect. Here we design and engineer matrices that recapitulate the key hallmarks of the PDAC tumour extracellular matrix to address this knowledge gap. We show that patient-derived PDAC organoids from three patients develop resistance to several clinically relevant chemotherapies when cultured within high-stiffness matrices mechanically matched to in vivo tumours. Using genetic barcoding, we find that while matrix-specific clonal selection occurs, cellular heterogeneity is not the main driver of chemoresistance. Instead, matrix-induced chemoresistance occurs within a stiff environment due to the increased expression of drug efflux transporters mediated by CD44 receptor interactions with hyaluronan. Moreover, PDAC chemoresistance is reversible following transfer from high- to low-stiffness matrices, suggesting that targeting the fibrotic extracellular matrix may sensitize chemoresistant tumours. Overall, our findings support the potential of engineered matrices and patient-derived organoids for elucidating extracellular matrix contributions to human disease pathophysiology. Patient-derived pancreatic cancer organoids grown in engineered matrices acquire chemoresistance due to the increased expression of drug efflux transporters, promoted by CD44 receptor interactions with hyaluronan in the stiffer tumoural matrix.","PeriodicalId":19058,"journal":{"name":"Nature Materials","volume":null,"pages":null},"PeriodicalIF":37.2000,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Engineered matrices reveal stiffness-mediated chemoresistance in patient-derived pancreatic cancer organoids\",\"authors\":\"Bauer L. LeSavage, Daiyao Zhang, Carla Huerta-López, Aidan E. Gilchrist, Brad A. Krajina, Kasper Karlsson, Amber R. Smith, Kremena Karagyozova, Katarina C. Klett, Michelle S. Huang, Christopher Long, Gernot Kaber, Christopher M. Madl, Paul L. Bollyky, Christina Curtis, Calvin J. Kuo, Sarah C. Heilshorn\",\"doi\":\"10.1038/s41563-024-01908-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Pancreatic ductal adenocarcinoma (PDAC) is characterized by its fibrotic and stiff extracellular matrix. However, how the altered cell/extracellular-matrix signalling contributes to the PDAC tumour phenotype has been difficult to dissect. Here we design and engineer matrices that recapitulate the key hallmarks of the PDAC tumour extracellular matrix to address this knowledge gap. We show that patient-derived PDAC organoids from three patients develop resistance to several clinically relevant chemotherapies when cultured within high-stiffness matrices mechanically matched to in vivo tumours. Using genetic barcoding, we find that while matrix-specific clonal selection occurs, cellular heterogeneity is not the main driver of chemoresistance. Instead, matrix-induced chemoresistance occurs within a stiff environment due to the increased expression of drug efflux transporters mediated by CD44 receptor interactions with hyaluronan. Moreover, PDAC chemoresistance is reversible following transfer from high- to low-stiffness matrices, suggesting that targeting the fibrotic extracellular matrix may sensitize chemoresistant tumours. Overall, our findings support the potential of engineered matrices and patient-derived organoids for elucidating extracellular matrix contributions to human disease pathophysiology. Patient-derived pancreatic cancer organoids grown in engineered matrices acquire chemoresistance due to the increased expression of drug efflux transporters, promoted by CD44 receptor interactions with hyaluronan in the stiffer tumoural matrix.\",\"PeriodicalId\":19058,\"journal\":{\"name\":\"Nature Materials\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":37.2000,\"publicationDate\":\"2024-07-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Materials\",\"FirstCategoryId\":\"88\",\"ListUrlMain\":\"https://www.nature.com/articles/s41563-024-01908-x\",\"RegionNum\":1,\"RegionCategory\":\"材料科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, PHYSICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Materials","FirstCategoryId":"88","ListUrlMain":"https://www.nature.com/articles/s41563-024-01908-x","RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}
Engineered matrices reveal stiffness-mediated chemoresistance in patient-derived pancreatic cancer organoids
Pancreatic ductal adenocarcinoma (PDAC) is characterized by its fibrotic and stiff extracellular matrix. However, how the altered cell/extracellular-matrix signalling contributes to the PDAC tumour phenotype has been difficult to dissect. Here we design and engineer matrices that recapitulate the key hallmarks of the PDAC tumour extracellular matrix to address this knowledge gap. We show that patient-derived PDAC organoids from three patients develop resistance to several clinically relevant chemotherapies when cultured within high-stiffness matrices mechanically matched to in vivo tumours. Using genetic barcoding, we find that while matrix-specific clonal selection occurs, cellular heterogeneity is not the main driver of chemoresistance. Instead, matrix-induced chemoresistance occurs within a stiff environment due to the increased expression of drug efflux transporters mediated by CD44 receptor interactions with hyaluronan. Moreover, PDAC chemoresistance is reversible following transfer from high- to low-stiffness matrices, suggesting that targeting the fibrotic extracellular matrix may sensitize chemoresistant tumours. Overall, our findings support the potential of engineered matrices and patient-derived organoids for elucidating extracellular matrix contributions to human disease pathophysiology. Patient-derived pancreatic cancer organoids grown in engineered matrices acquire chemoresistance due to the increased expression of drug efflux transporters, promoted by CD44 receptor interactions with hyaluronan in the stiffer tumoural matrix.
期刊介绍:
Nature Materials is a monthly multi-disciplinary journal aimed at bringing together cutting-edge research across the entire spectrum of materials science and engineering. It covers all applied and fundamental aspects of the synthesis/processing, structure/composition, properties, and performance of materials. The journal recognizes that materials research has an increasing impact on classical disciplines such as physics, chemistry, and biology.
Additionally, Nature Materials provides a forum for the development of a common identity among materials scientists and encourages interdisciplinary collaboration. It takes an integrated and balanced approach to all areas of materials research, fostering the exchange of ideas between scientists involved in different disciplines.
Nature Materials is an invaluable resource for scientists in academia and industry who are active in discovering and developing materials and materials-related concepts. It offers engaging and informative papers of exceptional significance and quality, with the aim of influencing the development of society in the future.