A multiplexed in vivo approach to identify driver genes in small cell lung cancer
Summary: Small cell lung cancer (SCLC) is a lethal form of lung cancer. Here, we develop a quantitative multiplexed approach on the basis of lentiviral barcoding with somatic CRISPR-Cas9-mediated genome editing to functionally investigate candidate regulators of tumor initiation and growth in geneti...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-01-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723000013 |
| _version_ | 1797952743416004608 |
|---|---|
| author | Myung Chang Lee Hongchen Cai Christopher W. Murray Chuan Li Yan Ting Shue Laura Andrejka Andy L. He Alessandra M.E. Holzem Alexandros P. Drainas Julie H. Ko Garry L. Coles Christina Kong Shirley Zhu ChunFang Zhu Jason Wang Matt van de Rijn Dmitri A. Petrov Monte M. Winslow Julien Sage |
| author_facet | Myung Chang Lee Hongchen Cai Christopher W. Murray Chuan Li Yan Ting Shue Laura Andrejka Andy L. He Alessandra M.E. Holzem Alexandros P. Drainas Julie H. Ko Garry L. Coles Christina Kong Shirley Zhu ChunFang Zhu Jason Wang Matt van de Rijn Dmitri A. Petrov Monte M. Winslow Julien Sage |
| author_sort | Myung Chang Lee |
| collection | DOAJ |
| description | Summary: Small cell lung cancer (SCLC) is a lethal form of lung cancer. Here, we develop a quantitative multiplexed approach on the basis of lentiviral barcoding with somatic CRISPR-Cas9-mediated genome editing to functionally investigate candidate regulators of tumor initiation and growth in genetically engineered mouse models of SCLC. We found that naphthalene pre-treatment enhances lentiviral vector-mediated SCLC initiation, enabling high multiplicity of tumor clones for analysis through high-throughput sequencing methods. Candidate drivers of SCLC identified from a meta-analysis across multiple human SCLC genomic datasets were tested using this approach, which defines both positive and detrimental impacts of inactivating 40 genes across candidate pathways on SCLC development. This analysis and subsequent validation in human SCLC cells establish TSC1 in the PI3K-AKT-mTOR pathway as a robust tumor suppressor in SCLC. This approach should illuminate drivers of SCLC, facilitate the development of precision therapies for defined SCLC genotypes, and identify therapeutic targets. |
| first_indexed | 2024-04-10T22:52:11Z |
| format | Article |
| id | doaj.art-0a467d5273d64bf6976383eac519d5b0 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-10T22:52:11Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-0a467d5273d64bf6976383eac519d5b02023-01-15T04:21:49ZengElsevierCell Reports2211-12472023-01-01421111990A multiplexed in vivo approach to identify driver genes in small cell lung cancerMyung Chang Lee0Hongchen Cai1Christopher W. Murray2Chuan Li3Yan Ting Shue4Laura Andrejka5Andy L. He6Alessandra M.E. Holzem7Alexandros P. Drainas8Julie H. Ko9Garry L. Coles10Christina Kong11Shirley Zhu12ChunFang Zhu13Jason Wang14Matt van de Rijn15Dmitri A. Petrov16Monte M. Winslow17Julien Sage18Department of Pediatrics, Stanford University, 265 Campus Drive, SIM1 G2078, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USADepartment of Genetics, Stanford University, Stanford, CA 94305, USADepartment of Genetics, Stanford University, Stanford, CA 94305, USADepartment of Biology, Stanford University, Stanford, CA 94305, USADepartment of Pediatrics, Stanford University, 265 Campus Drive, SIM1 G2078, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USADepartment of Genetics, Stanford University, Stanford, CA 94305, USADepartment of Pediatrics, Stanford University, 265 Campus Drive, SIM1 G2078, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USADepartment of Pediatrics, Stanford University, 265 Campus Drive, SIM1 G2078, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USADepartment of Pediatrics, Stanford University, 265 Campus Drive, SIM1 G2078, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USADepartment of Pediatrics, Stanford University, 265 Campus Drive, SIM1 G2078, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USADepartment of Pediatrics, Stanford University, 265 Campus Drive, SIM1 G2078, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USADepartment of Pathology, Stanford University, Stanford, CA 94305, USADepartment of Pathology, Stanford University, Stanford, CA 94305, USADepartment of Pathology, Stanford University, Stanford, CA 94305, USADepartment of Pathology, Stanford University, Stanford, CA 94305, USADepartment of Pathology, Stanford University, Stanford, CA 94305, USADepartment of Biology, Stanford University, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USADepartment of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USADepartment of Pediatrics, Stanford University, 265 Campus Drive, SIM1 G2078, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; Corresponding authorSummary: Small cell lung cancer (SCLC) is a lethal form of lung cancer. Here, we develop a quantitative multiplexed approach on the basis of lentiviral barcoding with somatic CRISPR-Cas9-mediated genome editing to functionally investigate candidate regulators of tumor initiation and growth in genetically engineered mouse models of SCLC. We found that naphthalene pre-treatment enhances lentiviral vector-mediated SCLC initiation, enabling high multiplicity of tumor clones for analysis through high-throughput sequencing methods. Candidate drivers of SCLC identified from a meta-analysis across multiple human SCLC genomic datasets were tested using this approach, which defines both positive and detrimental impacts of inactivating 40 genes across candidate pathways on SCLC development. This analysis and subsequent validation in human SCLC cells establish TSC1 in the PI3K-AKT-mTOR pathway as a robust tumor suppressor in SCLC. This approach should illuminate drivers of SCLC, facilitate the development of precision therapies for defined SCLC genotypes, and identify therapeutic targets.http://www.sciencedirect.com/science/article/pii/S2211124723000013CP: Cancer |
| spellingShingle | Myung Chang Lee Hongchen Cai Christopher W. Murray Chuan Li Yan Ting Shue Laura Andrejka Andy L. He Alessandra M.E. Holzem Alexandros P. Drainas Julie H. Ko Garry L. Coles Christina Kong Shirley Zhu ChunFang Zhu Jason Wang Matt van de Rijn Dmitri A. Petrov Monte M. Winslow Julien Sage A multiplexed in vivo approach to identify driver genes in small cell lung cancer Cell Reports CP: Cancer |
| title | A multiplexed in vivo approach to identify driver genes in small cell lung cancer |
| title_full | A multiplexed in vivo approach to identify driver genes in small cell lung cancer |
| title_fullStr | A multiplexed in vivo approach to identify driver genes in small cell lung cancer |
| title_full_unstemmed | A multiplexed in vivo approach to identify driver genes in small cell lung cancer |
| title_short | A multiplexed in vivo approach to identify driver genes in small cell lung cancer |
| title_sort | multiplexed in vivo approach to identify driver genes in small cell lung cancer |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723000013 |
| work_keys_str_mv | AT myungchanglee amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT hongchencai amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT christopherwmurray amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT chuanli amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT yantingshue amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT lauraandrejka amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT andylhe amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT alessandrameholzem amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT alexandrospdrainas amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT juliehko amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT garrylcoles amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT christinakong amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT shirleyzhu amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT chunfangzhu amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT jasonwang amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT mattvanderijn amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT dmitriapetrov amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT montemwinslow amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT juliensage amultiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT myungchanglee multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT hongchencai multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT christopherwmurray multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT chuanli multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT yantingshue multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT lauraandrejka multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT andylhe multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT alessandrameholzem multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT alexandrospdrainas multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT juliehko multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT garrylcoles multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT christinakong multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT shirleyzhu multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT chunfangzhu multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT jasonwang multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT mattvanderijn multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT dmitriapetrov multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT montemwinslow multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer AT juliensage multiplexedinvivoapproachtoidentifydrivergenesinsmallcelllungcancer |