Synapse - Recurrent WWTR1 S89W mutations and Hippo pathway deregulation in clear cell carcinomas of the cervix

Recurrent WWTR1 S89W mutations and Hippo pathway deregulation in clear cell carcinomas of the cervix Journal Article

Authors:	Kim, S. H.; Basili, T.; Dopeso, H.; Da Cruz Paula, A.; Bi, R.; Issa Bhaloo, S.; Pareja, F.; Li, Q.; da Silva, E. M.; Zhu, Y.; Hoang, T.; Selenica, P.; Murali, R.; Chan, E.; Wu, M.; Derakhshan, F.; Maroldi, A.; Hanlon, E.; Ferreira, C. G.; Lapa e Silva, J. R.; Abu-Rustum, N. R.; Zamarin, D.; Chandarlapaty, S.; Matrai, C.; Yoon, J. Y.; Reis-Filho, J. S.; Park, K. J.; Weigelt, B.
Article Title:	Recurrent WWTR1 S89W mutations and Hippo pathway deregulation in clear cell carcinomas of the cervix
Abstract:	Clear cell carcinoma (CCC) of the cervix (cCCC) is a rare and aggressive type of human papillomavirus (HPV)-negative cervical cancer with limited effective treatment options for recurrent or metastatic disease. Historically, CCCs of the lower genital tract were associated with in utero diethylstilbestrol exposure; however, the genetic landscape of sporadic cCCCs remains unknown. Here we sought to define the molecular underpinning of cCCCs. Using a combination of whole-exome, targeted capture, and RNA-sequencing, we identified pathogenic genetic alterations in the Hippo signaling pathway in 50% (10/20) of cCCCs, including recurrent WWTR1 S89W somatic mutations in 40% (4/10) of the cases harboring mutations in the Hippo pathway. Irrespective of the presence or absence of Hippo pathway genetic alterations, however, all primary cCCCs analyzed in this study (n = 20) harbored features of Hippo pathway deregulation at the transcriptomic and protein levels. In vitro functional analysis revealed that expression of the WWTR1 S89W mutation leads to reduced binding of TAZ to 14-3-3, promoting constitutive nuclear translocation of TAZ and Hippo pathway repression. WWTR1 S89W expression was found to lead to acquisition of oncogenic behavior, including increased proliferation, migration, and colony formation in vitro as well as increased tumorigenesis in vivo, which could be reversed by targeted inhibition of the TAZ/YAP1 complex with verteporfin. Finally, xenografts expressing WWTR1 S89W displayed a shift in tumor phenotype, becoming more infiltrative as well as less differentiated, and were found to be composed of cells with conspicuous cytoplasmic clearing as compared to controls. Our results demonstrate that Hippo pathway alterations are likely drivers of cCCCs and likely contribute to the clear cell phenotype. Therapies targeting this pathway may constitute a new class of treatment for these rare, aggressive tumors. © 2022 The Pathological Society of Great Britain and Ireland. © 2022 The Pathological Society of Great Britain and Ireland.
Keywords:	signal transduction; genetics; mutation; metabolism; physiology; carcinogenesis; signal peptide; intracellular signaling peptides and proteins; transactivator protein; trans-activators; cervix; uterine cervix; cervix uteri; hippo pathway; massively parallel sequencing; clear cell; hippo signaling pathway; humans; human; female; hippo signaling; wwtr1; wwtr1 protein, human; transcriptional coactivator with pdz-binding motif proteins
Journal Title:	Journal of Pathology
Volume:	257
Issue:	5
ISSN:	0022-3417
Publisher:	Wiley Blackwell
Date Published:	2022-08-01
Start Page:	635
End Page:	649
Language:	English
DOI:	10.1002/path.5910
PUBMED:	35411948
PROVIDER:	scopus
PMCID:	PMC9881397
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85130218797&doi=10.1002%2fpath.5910&partnerID=40&md5=cff20507d0395ec9a1fef41023b5c549
Notes:	Article -- Export Date: 2 September 2022 -- Source: Scopus