Matteo Villa, Geeta G Sharma, Federica Malighetti, Mario Mauri, Giulia Arosio, Nicoletta Cordani, Cosimo Lobello, Hugo Larose, Alessandra Pirola, Deborah D'Aliberti, Luca Massimino, Lucrezia Criscuolo, Lisa Pagani, Clizia Chinello, Cristina Mastini, Diletta Fontana, Silvia Bombelli, Raffaella Meneveri, Federica Lovisa, Lara Mussolin, Andrea Janikova, Šárka Pospíšilová, Suzanne D Turner, Giorgio Inghirami, Fulvio Magni, Mario Urso, Fabio Pagni, Daniele Ramazzotti, Rocco Piazza, Roberto Chiarle, Carlo Gambacorti-Passerini, Luca Mologni
{"title":"FAT家族粘附素的复发性体细胞突变会诱发无性大细胞淋巴瘤的侵袭性表型和不良预后。","authors":"Matteo Villa, Geeta G Sharma, Federica Malighetti, Mario Mauri, Giulia Arosio, Nicoletta Cordani, Cosimo Lobello, Hugo Larose, Alessandra Pirola, Deborah D'Aliberti, Luca Massimino, Lucrezia Criscuolo, Lisa Pagani, Clizia Chinello, Cristina Mastini, Diletta Fontana, Silvia Bombelli, Raffaella Meneveri, Federica Lovisa, Lara Mussolin, Andrea Janikova, Šárka Pospíšilová, Suzanne D Turner, Giorgio Inghirami, Fulvio Magni, Mario Urso, Fabio Pagni, Daniele Ramazzotti, Rocco Piazza, Roberto Chiarle, Carlo Gambacorti-Passerini, Luca Mologni","doi":"10.1038/s41416-024-02881-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Anaplastic Large Cell Lymphoma (ALCL) is a rare and aggressive T-cell lymphoma, classified into ALK-positive and ALK-negative subtypes, based on the presence of chromosomal translocations involving the ALK gene. The current standard of treatment for ALCL is polychemotherapy, with a high overall survival rate. However, a subset of patients does not respond to or develops resistance to these therapies, posing a serious challenge for clinicians. Recent targeted treatments such as ALK kinase inhibitors and anti-CD30 antibody-drug conjugates have shown promise but, for a fraction of patients, the prognosis is still unsatisfactory.</p><p><strong>Methods: </strong>We investigated the genetic landscape of ALK + ALCL by whole-exome sequencing; recurring mutations were characterized in vitro and in vivo using transduced ALCL cellular models.</p><p><strong>Results: </strong>Recurrent mutations in FAT family genes and the transcription factor RUNX1T1 were found. These mutations induced changes in ALCL cells morphology, growth, and migration, shedding light on potential factors contributing to treatment resistance. In particular, FAT4 silencing in ALCL cells activated the β-catenin and YAP1 pathways, which play crucial roles in tumor growth, and conferred resistance to chemotherapy. Furthermore, STAT1 and STAT3 were hyper-activated in these cells. Gene expression profiling showed global changes in pathways related to cell adhesion, cytoskeletal organization, and oncogenic signaling. Notably, FAT mutations associated with poor outcome in patients.</p><p><strong>Conclusions: </strong>These findings provide novel insights into the molecular portrait of ALCL, that could help improve treatment strategies and the prognosis for ALCL patients.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":null,"pages":null},"PeriodicalIF":6.4000,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Recurrent somatic mutations of FAT family cadherins induce an aggressive phenotype and poor prognosis in anaplastic large cell lymphoma.\",\"authors\":\"Matteo Villa, Geeta G Sharma, Federica Malighetti, Mario Mauri, Giulia Arosio, Nicoletta Cordani, Cosimo Lobello, Hugo Larose, Alessandra Pirola, Deborah D'Aliberti, Luca Massimino, Lucrezia Criscuolo, Lisa Pagani, Clizia Chinello, Cristina Mastini, Diletta Fontana, Silvia Bombelli, Raffaella Meneveri, Federica Lovisa, Lara Mussolin, Andrea Janikova, Šárka Pospíšilová, Suzanne D Turner, Giorgio Inghirami, Fulvio Magni, Mario Urso, Fabio Pagni, Daniele Ramazzotti, Rocco Piazza, Roberto Chiarle, Carlo Gambacorti-Passerini, Luca Mologni\",\"doi\":\"10.1038/s41416-024-02881-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Anaplastic Large Cell Lymphoma (ALCL) is a rare and aggressive T-cell lymphoma, classified into ALK-positive and ALK-negative subtypes, based on the presence of chromosomal translocations involving the ALK gene. The current standard of treatment for ALCL is polychemotherapy, with a high overall survival rate. However, a subset of patients does not respond to or develops resistance to these therapies, posing a serious challenge for clinicians. Recent targeted treatments such as ALK kinase inhibitors and anti-CD30 antibody-drug conjugates have shown promise but, for a fraction of patients, the prognosis is still unsatisfactory.</p><p><strong>Methods: </strong>We investigated the genetic landscape of ALK + ALCL by whole-exome sequencing; recurring mutations were characterized in vitro and in vivo using transduced ALCL cellular models.</p><p><strong>Results: </strong>Recurrent mutations in FAT family genes and the transcription factor RUNX1T1 were found. These mutations induced changes in ALCL cells morphology, growth, and migration, shedding light on potential factors contributing to treatment resistance. In particular, FAT4 silencing in ALCL cells activated the β-catenin and YAP1 pathways, which play crucial roles in tumor growth, and conferred resistance to chemotherapy. Furthermore, STAT1 and STAT3 were hyper-activated in these cells. Gene expression profiling showed global changes in pathways related to cell adhesion, cytoskeletal organization, and oncogenic signaling. Notably, FAT mutations associated with poor outcome in patients.</p><p><strong>Conclusions: </strong>These findings provide novel insights into the molecular portrait of ALCL, that could help improve treatment strategies and the prognosis for ALCL patients.</p>\",\"PeriodicalId\":9243,\"journal\":{\"name\":\"British Journal of Cancer\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.4000,\"publicationDate\":\"2024-10-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"British Journal of Cancer\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41416-024-02881-7\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"British Journal of Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41416-024-02881-7","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Recurrent somatic mutations of FAT family cadherins induce an aggressive phenotype and poor prognosis in anaplastic large cell lymphoma.
Background: Anaplastic Large Cell Lymphoma (ALCL) is a rare and aggressive T-cell lymphoma, classified into ALK-positive and ALK-negative subtypes, based on the presence of chromosomal translocations involving the ALK gene. The current standard of treatment for ALCL is polychemotherapy, with a high overall survival rate. However, a subset of patients does not respond to or develops resistance to these therapies, posing a serious challenge for clinicians. Recent targeted treatments such as ALK kinase inhibitors and anti-CD30 antibody-drug conjugates have shown promise but, for a fraction of patients, the prognosis is still unsatisfactory.
Methods: We investigated the genetic landscape of ALK + ALCL by whole-exome sequencing; recurring mutations were characterized in vitro and in vivo using transduced ALCL cellular models.
Results: Recurrent mutations in FAT family genes and the transcription factor RUNX1T1 were found. These mutations induced changes in ALCL cells morphology, growth, and migration, shedding light on potential factors contributing to treatment resistance. In particular, FAT4 silencing in ALCL cells activated the β-catenin and YAP1 pathways, which play crucial roles in tumor growth, and conferred resistance to chemotherapy. Furthermore, STAT1 and STAT3 were hyper-activated in these cells. Gene expression profiling showed global changes in pathways related to cell adhesion, cytoskeletal organization, and oncogenic signaling. Notably, FAT mutations associated with poor outcome in patients.
Conclusions: These findings provide novel insights into the molecular portrait of ALCL, that could help improve treatment strategies and the prognosis for ALCL patients.
期刊介绍:
The British Journal of Cancer is one of the most-cited general cancer journals, publishing significant advances in translational and clinical cancer research.It also publishes high-quality reviews and thought-provoking comment on all aspects of cancer prevention,diagnosis and treatment.