Rlf–Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer
<jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may h...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Association for Cancer Research (AACR)
2022
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| Online Access: | https://hdl.handle.net/1721.1/146820 |
| _version_ | 1826214949187223552 |
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| author | Ciampricotti, Metamia Karakousi, Triantafyllia Richards, Allison L Quintanal-Villalonga, Àlvaro Karatza, Angeliki Caeser, Rebecca Costa, Emily A Allaj, Viola Manoj, Parvathy Spainhower, Kyle B Kombak, Faruk E Sanchez-Rivera, Francisco J Jaspers, Janneke E Zavitsanou, Anastasia-Maria Maddalo, Danilo Ventura, Andrea Rideout, William M Akama-Garren, Elliot H Jacks, Tyler Donoghue, Mark TA Sen, Triparna Oliver, Trudy G Poirier, John T Papagiannakopoulos, Thales Rudin, Charles M |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Ciampricotti, Metamia Karakousi, Triantafyllia Richards, Allison L Quintanal-Villalonga, Àlvaro Karatza, Angeliki Caeser, Rebecca Costa, Emily A Allaj, Viola Manoj, Parvathy Spainhower, Kyle B Kombak, Faruk E Sanchez-Rivera, Francisco J Jaspers, Janneke E Zavitsanou, Anastasia-Maria Maddalo, Danilo Ventura, Andrea Rideout, William M Akama-Garren, Elliot H Jacks, Tyler Donoghue, Mark TA Sen, Triparna Oliver, Trudy G Poirier, John T Papagiannakopoulos, Thales Rudin, Charles M |
| author_sort | Ciampricotti, Metamia |
| collection | MIT |
| description | <jats:title>Abstract</jats:title>
<jats:sec>
<jats:title />
<jats:p>Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may help define novel therapeutic targets. Recurrent genomic rearrangements have been identified in SCLC, most notably an in-frame gene fusion between RLF and MYCL found in up to 7% of the predominant ASCL1-expressing subtype. To explore the role of this fusion in oncogenesis and tumor progression, we used CRISPR/Cas9 somatic editing to generate a Rlf–Mycl-driven mouse model of SCLC. RLF–MYCL fusion accelerated transformation and proliferation of murine SCLC and increased metastatic dissemination and the diversity of metastatic sites. Tumors from the RLF–MYCL genetically engineered mouse model displayed gene expression similarities with human RLF–MYCL SCLC. Together, our studies support RLF–MYCL as the first demonstrated fusion oncogenic driver in SCLC and provide a new preclinical mouse model for the study of this subtype of SCLC.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Significance:</jats:title>
<jats:p>The biological and therapeutic implications of gene fusions in SCLC, an aggressive metastatic lung cancer, are unknown. Our study investigates the functional significance of the in-frame RLF–MYCL gene fusion by developing a Rlf–Mycl-driven genetically engineered mouse model and defining the impact on tumor growth and metastasis.</jats:p>
<jats:p>This article is highlighted in the In This Issue feature, p. 2945</jats:p>
</jats:sec> |
| first_indexed | 2024-09-23T16:14:05Z |
| format | Article |
| id | mit-1721.1/146820 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T16:14:05Z |
| publishDate | 2022 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1468202022-12-10T03:02:27Z Rlf–Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer Ciampricotti, Metamia Karakousi, Triantafyllia Richards, Allison L Quintanal-Villalonga, Àlvaro Karatza, Angeliki Caeser, Rebecca Costa, Emily A Allaj, Viola Manoj, Parvathy Spainhower, Kyle B Kombak, Faruk E Sanchez-Rivera, Francisco J Jaspers, Janneke E Zavitsanou, Anastasia-Maria Maddalo, Danilo Ventura, Andrea Rideout, William M Akama-Garren, Elliot H Jacks, Tyler Donoghue, Mark TA Sen, Triparna Oliver, Trudy G Poirier, John T Papagiannakopoulos, Thales Rudin, Charles M Massachusetts Institute of Technology. Department of Biology <jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may help define novel therapeutic targets. Recurrent genomic rearrangements have been identified in SCLC, most notably an in-frame gene fusion between RLF and MYCL found in up to 7% of the predominant ASCL1-expressing subtype. To explore the role of this fusion in oncogenesis and tumor progression, we used CRISPR/Cas9 somatic editing to generate a Rlf–Mycl-driven mouse model of SCLC. RLF–MYCL fusion accelerated transformation and proliferation of murine SCLC and increased metastatic dissemination and the diversity of metastatic sites. Tumors from the RLF–MYCL genetically engineered mouse model displayed gene expression similarities with human RLF–MYCL SCLC. Together, our studies support RLF–MYCL as the first demonstrated fusion oncogenic driver in SCLC and provide a new preclinical mouse model for the study of this subtype of SCLC.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>The biological and therapeutic implications of gene fusions in SCLC, an aggressive metastatic lung cancer, are unknown. Our study investigates the functional significance of the in-frame RLF–MYCL gene fusion by developing a Rlf–Mycl-driven genetically engineered mouse model and defining the impact on tumor growth and metastasis.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 2945</jats:p> </jats:sec> 2022-12-09T18:43:20Z 2022-12-09T18:43:20Z 2021 2022-12-09T18:36:27Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/146820 Ciampricotti, Metamia, Karakousi, Triantafyllia, Richards, Allison L, Quintanal-Villalonga, Àlvaro, Karatza, Angeliki et al. 2021. "Rlf–Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer." Cancer Discovery, 11 (12). en 10.1158/2159-8290.CD-21-0441 Cancer Discovery Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) PMC |
| spellingShingle | Ciampricotti, Metamia Karakousi, Triantafyllia Richards, Allison L Quintanal-Villalonga, Àlvaro Karatza, Angeliki Caeser, Rebecca Costa, Emily A Allaj, Viola Manoj, Parvathy Spainhower, Kyle B Kombak, Faruk E Sanchez-Rivera, Francisco J Jaspers, Janneke E Zavitsanou, Anastasia-Maria Maddalo, Danilo Ventura, Andrea Rideout, William M Akama-Garren, Elliot H Jacks, Tyler Donoghue, Mark TA Sen, Triparna Oliver, Trudy G Poirier, John T Papagiannakopoulos, Thales Rudin, Charles M Rlf–Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer |
| title | Rlf–Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer |
| title_full | Rlf–Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer |
| title_fullStr | Rlf–Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer |
| title_full_unstemmed | Rlf–Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer |
| title_short | Rlf–Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer |
| title_sort | rlf mycl gene fusion drives tumorigenesis and metastasis in a mouse model of small cell lung cancer |
| url | https://hdl.handle.net/1721.1/146820 |
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