Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer
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Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer
Yale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Development Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer t Of Pancreatic Cancer Organoid Model For Studying Immune Response In Pancreatic CancerJin Woo YooFollow this and additional works at: https://elischolar.library.yale.edu/ymtdlRecommended CitationYoo, Jin Ubo, "Development Of Pancreatic Cancer Organoid Model For Studying Immune Response In Pancreati Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer c Cancer' (2019).Yale bMiánỉ TJie-Mi DigHal Library. 3543.https://eliicholar.library.yaIe.edu.i’ymtdl/3S43lh»i Open Acceii Ibnu i* brought to you forLuận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer
free and open access by the School of Xiedxinc at EhSchobr - A Digital Platform for Scholarly Publishing at Yale. It h» been accepted for ĩnduõon in YYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Development Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer ation, plcate contact eliM.-hciirfSyale.edu.Development of Pancreatic Cancer 01 ganoid Models for Studying Illumine Response in Pancreatic CancerA Thesis Submined to theYale University School of Medicine in Partial Fulfillment of the Requirements for theDegree of Doctor of MedicinebyJin Woo Yoo2019D Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer FATI.OPMENT OF PANCREATIC CANCER ORGANOID MODEL FOR STUDYING IMMUNE RESPONSE IN PANCREATIC CANCER. Jin Woo Yoo. Prashanth R Gokaie. Yevgeniya Foster.Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer
Brittany Fitzgerald. Nikhil s. Joshi, James J. Farrell. Section of Gastroenterology, Department of hit dual Medicine, Yale University, School of MedicYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Development Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer ly due to the lack of effective model systems. Cell lines are not physiologic as they cannot recapitulate the cancer stroma and lose genetic heterogeneity over tunc. Genetically engineered mouse models of PDAC are more physiologic than cell lines bur lack neoantigens needed to mount T cell responses Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer against tumor. Organoid models of PDAC offer unique opportunity to study immune mechanisms 111 PDAC since organoids can model complex layering of mulLuận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer
tiple cell types, creating a physiologically relevant system that IS highly tractable for genetic manipulation, co-cultures. and high throughput assayYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Development Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer c aims of developing transplantable immunogenic murine PDAC organoid models for the study of antigenspecific anti-tumor T cell responses and assembling a library of experimentally validated, patient-derived PDAC organoid lines foi pancreatic cancer piccision medicine research.To generate immunogenic Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer murine organoid models of PDAC. pancreatic organoids were isolated Jjom “KP-N1NJA” (KrasLvit'SiOl,’Lux’eiJD:inversion induced joinedneoantigen) mouseLuận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer
model that has been genetically engineered to express GFP-tagged T cell neoantigens derived from lymphocytic choriomeningitis vims in an inducible faYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Development Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer KRAS and deletion of P53. A subset of transformed organoids was additionally treated with an adenoviral construct encoding FLPo recombinase to turn on neoantigen expression. Transformed organoids were combined with T cells m both in vivo and in vitro setting to assess for impact on tumor growth. Pat Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer ient-derived PDAC organoids were generated using endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) specimens, surgical resection specimens, anLuận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer
d tissues from patient-derived xenograft mouse models of PDAC. Established human organoid lines were validated by Sanger sequencing, tumor formation iYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Development Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer histologically similar to early lesions found in human PDAC. Serial in VIVO transfer of these organoids by performing sequential rounds of organoid generation from rumors derived from organoids formed progressively more advanced tumors. High level of neoantigen expression in 100% of cells comprisin Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer g murine PDAC organoids resulted in rejection of tumor growth in mouse, while a low level of neoantigen expression restricted to 10% of cells permitteLuận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer
d tumor growth with increased immune infiltration Expression of neoantigens in T cell-PDAC organoid co-cultiue model systems promoted T cell infiltratYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Development Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer 10 2017 to 5/2018.We have successfully established mill ine and human organoid models of PDAC from various tissues capturing discrete stages of PDAC progression. Our murine organoid models are uniquely equipped to study antigen-specific T cell responses against tumor. Ongoing work includes using CRI Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer SPR Cas9-based lentiviral systems to define genes that impact anti-tumor T cell responses and using patient-derived organoids for precision medicine rLuận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer
esearch.ACKNOWLEDGEMENTSWork fol this thesis was completed ill the Joshi laboratory under the co-mentorship of James J. Farrell. MD and Nikhil s. JoshYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Development Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer ental for the creation of immunogenic murine PDAC organoid models. Dr. Farrell perfbiined and provided all the endoscopic ultrasound-guided fine-needle biopsies for the creation of patient-derived PDAC organoid lilies. Prashanth Gokare. PhD collaborated with the author on the development of tliree-d Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer imensional co-culture system for murine pancreatic cancer organoids and T cells and the creation of patient-derived PDAC organoids from surgical resecLuận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer
tion specimens and then sequencing. Yevgemya Foster. MD collaborated with the author on creation of immunogenic murine PDAC organoid lines for charactYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Development Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer e pancreatic cancer cell lines from KP-C mouse and collaborated with the author on 111 vivo transfer of P14 mouse splenocytes and 111 vivo imaging for luciferase detection Marie Robert. MD provided surgical resection specimens for creation of patient-derived pancreatic cancer organoids and interpret Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer ation of tiunor histology. Ryan Sowell. PhD fl0111 Kaech laboratory created the patient-derived xenograft mouse models, some of which were used as sorLuận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer
uce material for the creation of human PDAC organoids. All other experiments were pel formed independently by the author. Dr. Farrell and Di Joshi revYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Development Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer tudent Research Fellowship (T35 giant). Yale University School of Medicine Research Fellowship, and Richard Alan HirsliField Memorial Fellowship provided funding to support this work.TABLE OF CONTENTSLIST OF ABBREVIATIONS............................................1INTRODUCTION...................... Luận văn thạc sĩ development of pancreatic cancer organoid model for studying immune response in pancreatic cancer ...............................2•BackgroundYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466DevelopmentYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466DevelopmentGọi ngay
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