Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label therapy
Summary: Pancreatic cancer (PDAC) is a highly aggressive malignancy for which the identification of novel therapies is urgently needed. Here, we establish a human PDAC organoid biobank from 31 genetically distinct lines, covering a representative range of tumor subtypes, and demonstrate that these r...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-02-01
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| Series: | Cell Genomics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666979X2200012X |
| _version_ | 1797776647660765184 |
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| author | Christian K. Hirt Tijmen H. Booij Linda Grob Patrik Simmler Nora C. Toussaint David Keller Doreen Taube Vanessa Ludwig Alexander Goryachkin Chantal Pauli Daniela Lenggenhager Daniel J. Stekhoven Christian U. Stirnimann Katharina Endhardt Femke Ringnalda Lukas Villiger Alexander Siebenhüner Sofia Karkampouna Marta De Menna Janette Beshay Hagen Klett Marianna Kruithof-de Julio Julia Schüler Gerald Schwank |
| author_facet | Christian K. Hirt Tijmen H. Booij Linda Grob Patrik Simmler Nora C. Toussaint David Keller Doreen Taube Vanessa Ludwig Alexander Goryachkin Chantal Pauli Daniela Lenggenhager Daniel J. Stekhoven Christian U. Stirnimann Katharina Endhardt Femke Ringnalda Lukas Villiger Alexander Siebenhüner Sofia Karkampouna Marta De Menna Janette Beshay Hagen Klett Marianna Kruithof-de Julio Julia Schüler Gerald Schwank |
| author_sort | Christian K. Hirt |
| collection | DOAJ |
| description | Summary: Pancreatic cancer (PDAC) is a highly aggressive malignancy for which the identification of novel therapies is urgently needed. Here, we establish a human PDAC organoid biobank from 31 genetically distinct lines, covering a representative range of tumor subtypes, and demonstrate that these reflect the molecular and phenotypic heterogeneity of primary PDAC tissue. We use CRISPR-Cas9 genome editing and drug screening to characterize drug-gene interactions with ARID1A and BRCA2. We find that missense, but not frameshift, mutations in the PDAC driver gene ARID1A are associated with increased sensitivity to the kinase inhibitors dasatinib (p < 0.0001) and VE-821 (p < 0.0001). We further conduct an automated drug-repurposing screen with 1,172 FDA-approved compounds, identifying 26 compounds that effectively kill PDAC organoids, including 19 chemotherapy drugs currently approved for other cancer types. We validate the activity of these compounds in vitro and in vivo. The in vivo validated hits include emetine and ouabain, compounds that are approved for non-cancer indications and that perturb the ability of PDAC organoids to respond to hypoxia. Our study provides proof-of-concept for advancing precision oncology and for identifying candidates for drug repurposing via genome editing and drug screening in tumor organoid biobanks. |
| first_indexed | 2024-03-12T22:52:55Z |
| format | Article |
| id | doaj.art-528029a5e0b440e9b617944420259540 |
| institution | Directory Open Access Journal |
| issn | 2666-979X |
| language | English |
| last_indexed | 2024-03-12T22:52:55Z |
| publishDate | 2022-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Genomics |
| spelling | doaj.art-528029a5e0b440e9b6179444202595402023-07-20T04:39:15ZengElsevierCell Genomics2666-979X2022-02-0122100095Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label therapyChristian K. Hirt0Tijmen H. Booij1Linda Grob2Patrik Simmler3Nora C. Toussaint4David Keller5Doreen Taube6Vanessa Ludwig7Alexander Goryachkin8Chantal Pauli9Daniela Lenggenhager10Daniel J. Stekhoven11Christian U. Stirnimann12Katharina Endhardt13Femke Ringnalda14Lukas Villiger15Alexander Siebenhüner16Sofia Karkampouna17Marta De Menna18Janette Beshay19Hagen Klett20Marianna Kruithof-de Julio21Julia Schüler22Gerald Schwank23Institute of Molecular Health Sciences, ETH Zurich, Switzerland; Institute of Pharmacology and Toxicology, University Zurich, SwitzerlandNEXUS Personalized Health Technologies, ETH Zurich, SwitzerlandNEXUS Personalized Health Technologies, ETH Zurich, Switzerland; SIB Swiss Institute of Bioinformatics, Zurich, SwitzerlandInstitute of Molecular Health Sciences, ETH Zurich, Switzerland; Institute of Pharmacology and Toxicology, University Zurich, SwitzerlandNEXUS Personalized Health Technologies, ETH Zurich, Switzerland; SIB Swiss Institute of Bioinformatics, Zurich, SwitzerlandNEXUS Personalized Health Technologies, ETH Zurich, SwitzerlandInstitute of Molecular Health Sciences, ETH Zurich, SwitzerlandInstitute of Molecular Health Sciences, ETH Zurich, SwitzerlandInstitute of Molecular Health Sciences, ETH Zurich, SwitzerlandDepartment of Pathology and Molecular Pathology, University Hospital Zurich, SwitzerlandDepartment of Pathology and Molecular Pathology, University Hospital Zurich, SwitzerlandNEXUS Personalized Health Technologies, ETH Zurich, Switzerland; SIB Swiss Institute of Bioinformatics, Zurich, SwitzerlandNEXUS Personalized Health Technologies, ETH Zurich, SwitzerlandDepartment of Pathology and Molecular Pathology, University Hospital Zurich, SwitzerlandInstitute of Molecular Health Sciences, ETH Zurich, SwitzerlandInstitute of Molecular Health Sciences, ETH Zurich, Switzerland; Institute of Pharmacology and Toxicology, University Zurich, SwitzerlandComprehensive Cancer Center, University Hospital Zurich, SwitzerlandDepartment for BioMedical Research, Urology Research laboratory, University Bern, Switzerland; Department of Urology, Inselspital, Bern University Hospital, SwitzerlandDepartment for BioMedical Research, Urology Research laboratory, University Bern, Switzerland; Department of Urology, Inselspital, Bern University Hospital, SwitzerlandDiscovery Services, Oncotest, Charles River, Freiburg, GermanyDiscovery Services, Oncotest, Charles River, Freiburg, GermanyDepartment for BioMedical Research, Urology Research laboratory, University Bern, Switzerland; Department of Urology, Inselspital, Bern University Hospital, SwitzerlandDiscovery Services, Oncotest, Charles River, Freiburg, GermanyInstitute of Molecular Health Sciences, ETH Zurich, Switzerland; Institute of Pharmacology and Toxicology, University Zurich, Switzerland; Corresponding authorSummary: Pancreatic cancer (PDAC) is a highly aggressive malignancy for which the identification of novel therapies is urgently needed. Here, we establish a human PDAC organoid biobank from 31 genetically distinct lines, covering a representative range of tumor subtypes, and demonstrate that these reflect the molecular and phenotypic heterogeneity of primary PDAC tissue. We use CRISPR-Cas9 genome editing and drug screening to characterize drug-gene interactions with ARID1A and BRCA2. We find that missense, but not frameshift, mutations in the PDAC driver gene ARID1A are associated with increased sensitivity to the kinase inhibitors dasatinib (p < 0.0001) and VE-821 (p < 0.0001). We further conduct an automated drug-repurposing screen with 1,172 FDA-approved compounds, identifying 26 compounds that effectively kill PDAC organoids, including 19 chemotherapy drugs currently approved for other cancer types. We validate the activity of these compounds in vitro and in vivo. The in vivo validated hits include emetine and ouabain, compounds that are approved for non-cancer indications and that perturb the ability of PDAC organoids to respond to hypoxia. Our study provides proof-of-concept for advancing precision oncology and for identifying candidates for drug repurposing via genome editing and drug screening in tumor organoid biobanks.http://www.sciencedirect.com/science/article/pii/S2666979X2200012Xpancreatic cancerorganoidsdrug screeningPDXBRCA2ARID1A |
| spellingShingle | Christian K. Hirt Tijmen H. Booij Linda Grob Patrik Simmler Nora C. Toussaint David Keller Doreen Taube Vanessa Ludwig Alexander Goryachkin Chantal Pauli Daniela Lenggenhager Daniel J. Stekhoven Christian U. Stirnimann Katharina Endhardt Femke Ringnalda Lukas Villiger Alexander Siebenhüner Sofia Karkampouna Marta De Menna Janette Beshay Hagen Klett Marianna Kruithof-de Julio Julia Schüler Gerald Schwank Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label therapy Cell Genomics pancreatic cancer organoids drug screening PDX BRCA2 ARID1A |
| title | Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label therapy |
| title_full | Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label therapy |
| title_fullStr | Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label therapy |
| title_full_unstemmed | Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label therapy |
| title_short | Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label therapy |
| title_sort | drug screening and genome editing in human pancreatic cancer organoids identifies drug gene interactions and candidates for off label therapy |
| topic | pancreatic cancer organoids drug screening PDX BRCA2 ARID1A |
| url | http://www.sciencedirect.com/science/article/pii/S2666979X2200012X |
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