LATS2 is a tumor suppressor gene of malignant mesothelioma

Our plain-English summary of LATS2 is a tumor suppressor gene of malignant mesothelioma, by H. Murakami, T. Mizuno, T. Taniguchi, et al (Cancer Research, 2011).

The study

• Authors: H. Murakami, T. Mizuno, T. Taniguchi, M. Fujii, F. Ishiguro, T. Fukui, S. Akatsuka, Y. Horio, T. Hida, Y. Kondo, S. Toyokuni, H. Osada, Y. Sekido
• Journal: Cancer Research
• Published: 2011;71(3):873-83
• Cited by: 201 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. We carried out genome-wide array-based comparative genomic hybridization analysis with 14 MM cell lines. Three cell lines showed overlapping homozygous deletion at chromosome 13q12, which harbored the LATS2 (large tumor suppressor homolog 2) gene. With 6 other MM cell lines and 25 MM tumors, we found 10 inactivating homozygous deletions or mutations of LATS2 among 45 MMs. LATS2 encodes a serine/threonine kinase, a component of the Hippo tumor-suppressive signaling pathway, and we transduced LATS2 in MM cells with its mutation. Transduction of LATS2 inactivated oncoprotein YAP, a transcriptional coactivator, via phosphorylation, and inhibited MM cell growth. We also analyzed LATS2 immunohistochemically and found that 13 of 45 MM tumors had low expression of LATS2. Because NF2 is genetically mutated in 40% to 50% of MM, our data indicate that Hippo pathway dysregulation is frequent in MM cells with inactivation of LATS2 or an upstream regulator of this pathway, Merlin, which is encoded by NF2. Thus, our results suggest that the inactivation of LATS2 is one of the key mechanisms for constitutive activation of YAP, which induces deregulation of MM cell proliferation.

In plain English

This laboratory study examined faulty genes in malignant mesothelioma. The authors analyzed DNA from 20 mesothelioma cell lines (cancer cells grown in the lab, 14 of them from Japanese patients with malignant pleural mesothelioma) and from 25 primary tumors. They focused on LATS2, a gene in the Hippo signaling pathway, which normally restrains cell growth. LATS2 was deleted or mutated in 7 of 20 cell lines and in 3 (12%) of 25 tumors, 10 of 45 mesotheliomas (22%). In 16 (80%) of the 20 cell lines, the Merlin-Hippo pathway was considered inactivated. Putting a working LATS2 gene into cell lines with LATS2 mutations inactivated YAP, which the article calls an oncoprotein (cancer-promoting protein), and slowed cell growth. A mutant version of LATS2 did not. Staining of 45 primary mesotheliomas showed negative or weak LATS2 in 13 (29%). The authors concluded that LATS2 may be a tumor suppressor gene in mesothelioma. They suggested normal cells mixed into tumors may have hidden some changes; selection while establishing cell lines might instead explain the lower tumor rate. Asbestos exposure was not examined.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: genome-wide DNA analysis (array CGH) and gene sequencing of mesothelioma cell lines and tumors, gene-transfer experiments in cell lines, and immunohistochemical staining of tumor tissue
• Who was studied: 20 malignant mesothelioma cell lines: 14 Japanese malignant pleural mesothelioma lines established by the authors' laboratory plus 6 others. One immortalized non-cancerous mesothelial cell line (MeT-5A). 25 primary mesothelioma tumors, and 45 primary mesotheliomas for tissue staining. The tissue came from patients at five Japanese hospitals plus a commercial tissue array of 19 mesothelioma samples (US Biomax).
• Exposure: Not studied. The article reports no asbestos exposure information for the patients or cell lines. It studies genetic changes in the LATS2, NF2 and SAV1 genes.
• Main results:
  • Among the first 14 cell lines, 3 had a homozygous deletion (loss of both copies) at chromosome 13q12.11, which disrupted the LATS2 gene
  • Cell lines: 7 genetic mutations of LATS2 were found in 20 mesothelioma cell lines
  • Primary tumors: 3 (12%) of 25 had a genetic alteration that inactivates LATS2
  • Combined: LATS2 was genetically inactivated in 22% (10 of 45 mesotheliomas, counting the 20 cell lines and 25 primary tumors)
  • Among the 20 cell lines, 16 (80%) were considered to have an inactivated Merlin-Hippo pathway (through NF2, LATS2 or SAV1 changes, or loss of Merlin expression)
  • SAV1, another gene in the pathway, was homozygously deleted in one cell line (Y-MESO-28)
  • In cell lines lacking LATS2, adding back the normal gene led to phosphorylation of the YAP protein (which inactivates it)
  • The normal LATS2 gene, but not the mutant form, inhibited growth of mesothelioma cell lines with LATS2 mutation in the lab
  • Tissue staining of 45 primary mesotheliomas: 13 (29%) showed negative or weak LATS2 (2 negative, 11 weak)
  • Of the 45 primary mesotheliomas, 33 showed YAP staining in the nucleus stronger than or equal to that in the cytoplasm. The authors read this as constitutive YAP activation in more than 70%.
  • Of the 13 tumors with negative or weak LATS2 staining, 11 had stronger or equal YAP staining in the nucleus
• The authors' conclusion: The authors concluded that LATS2 may be a tumor suppressor gene in mesothelioma cells, and that the Hippo pathway can be inactivated by LATS2 mutation
• Limitations the authors state:
  • Primary tumors contain many normal cells, so the authors expected detection of gene loss or mutation in tumors to be less sensitive than in cell lines
  • Five tumors showed loss of LATS2, but contamination by normal cells meant the authors could not confirm a homozygous deletion in any of them
  • The higher mutation rate in cell lines than in tumors might instead reflect selection during establishment of the cell lines

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Tumor Suppressor Gene, Malignant Mesothelioma, Neoplasm, Asbestos Exposure, Homozygous Deletion, Merlin.

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• Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations — Y. Kadariya, M. Cheung, et al. (2016)
• Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma — S. Brich, F. Bozzi, et al. (2020)
• LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade — I. Tanaka, H. Osada, et al. (2015)
• Asbestos, chromosomal deletions, and tumor suppressor gene alterations in human malignant mesothelioma — S.S. Murthy, J.R. Testa (1999)

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