Cancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens

Our plain-English summary of Cancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens, by I.A.M. Barbosa, R. Gopalakrishnan, S. Mercan, et al (Nature Communications, 2023).

The study

• Authors: I.A.M. Barbosa, R. Gopalakrishnan, S. Mercan, T.P. Mourikis, T. Martin, S. Wengert, C. Sheng, F. Ji, R. Lopes, J. Knehr, M. Altorfer, A. Lindeman, C. Russ, U. Naumann, J. Golji, K. Sprouffske, L. Barys, L. Tordella, D. Schübeler, T. Schmelzle, G.G. Galli
• Journal: Nature Communications
• Published: 2023;14(1):3907
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

YAP is a key transcriptional co-activator of TEADs, it regulates cell growth and is frequently activated in cancer. In Malignant Pleural Mesothelioma (MPM), YAP is activated by loss-of-function mutations in upstream components of the Hippo pathway, while, in Uveal Melanoma (UM), YAP is activated in a Hippo-independent manner. To date, it is unclear if and how the different oncogenic lesions activating YAP impact its oncogenic program, which is particularly relevant for designing selective anti-cancer therapies. Here we show that, despite YAP being essential in both MPM and UM, its interaction with TEAD is unexpectedly dispensable in UM, limiting the applicability of TEAD inhibitors in this cancer type. Systematic functional interrogation of YAP regulatory elements in both cancer types reveals convergent regulation of broad oncogenic drivers in both MPM and UM, but also strikingly selective programs. Our work reveals unanticipated lineage-specific features of the YAP regulatory network that provide important insights to guide the design of tailored therapeutic strategies to inhibit YAP signaling across different cancer types.

© 2023. The Author(s).

In plain English

The experiments in this study were done in cancer cell lines; the authors also drew on public datasets, TCGA expression data from patient tumours and DepMap dependency scores from cell lines, and asbestos exposure was not studied. The authors compared how the protein YAP drives cell growth in malignant pleural mesothelioma (MPM) and uveal melanoma (UM) cell lines. Silencing YAP reduced proliferation in cell models of both lineages, but dependence on YAP's partner TEAD, measured both by a TEAD inhibitor and by silencing TEAD genes, was restricted to the mesothelioma models. The authors mapped where YAP sits on DNA and built a CRISPR interference library of about 160,000 guide RNAs targeting 18039 YAP peaks (2941 common to both lineages, 6389 mesothelioma-specific, 2119 uveal melanoma-specific), then a smaller 13,000-guide library screened in four cell lines. Some YAP-bound regulatory elements mattered in both lineages, while others were lineage-restricted, including separate MYC-locus enhancers 440 Kb (mesothelioma) and 1.8 Mb (uveal melanoma) downstream of the MYC start site, MAPK-related elements (JUN, FOSL1, FOSB) in mesothelioma, and PAX3, SOX10 and MITF elements in uveal melanoma.

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 (in vitro) molecular biology study in cancer cell lines: CRISPR interference functional epigenomic screens, ChIP-seq, Cut&Tag, HiC/HiChIP and drug-sensitivity assays, with secondary analyses of public TCGA tumour expression data and DepMap cell line dependency data
• Who was studied: Human cancer cell lines: mesothelioma (NCI-H2052, MSTO-211H, H226, Acc-Meso1), uveal melanoma (92.1, MEL202, MP41, OMM1) and lines of other lineages (lung, skin melanoma, pancreatic, liver); the primary screen used NCI-H2052 and 92.1, the validation screen four lines, two per lineage; public TCGA patient tumour expression data and DepMap cell line dependency data were also analysed
• Exposure: Not an exposure study: genetic perturbations (shRNA knockdown of YAP; CRISPRi silencing of YAP-bound regulatory elements and gene promoters) and drug treatments (a TEAD inhibitor alone and combined with MAPK-pathway inhibitors trametinib, erlotinib, an SHP2 inhibitor and naporafenib)
• Main results:
  • Knockdown of YAP reduced proliferation in both mesothelioma and uveal melanoma cell models
  • Dependence on TEAD, in the screens, was limited to the mesothelioma models
  • The screening library targeted 18039 YAP peaks, split between shared and lineage-specific peaks
  • Few guide RNAs differed significantly between the two screened lines at day 22 (311 for NCI-H2052, 1262 for 92.1, as printed)
  • Separate MYC-locus elements scored in each lineage: 440 Kb downstream in mesothelioma, 1.8 Mb downstream in uveal melanoma
  • In mesothelioma cells, YAP-bound elements sat in loci of MAPK-responsive transcription factors, and combining a TEAD inhibitor with MAPK-pathway inhibitors gave synergistic anti-proliferative effects in NCI-H2052 cells
  • In uveal melanoma cells, lineage-specific hits involved melanocytic master regulator loci
  • In public patient tumour data (TCGA), mesothelioma showed increased expression of several MAPK transcription factors
  • In public patient tumour data (TCGA), high expression of PAX3, SOX10, MITF and TFAP2A was reported as a defining feature of uveal melanoma patient samples, with these factors validated as dependencies in UM cell lines by large-scale functional genomics screens
• The authors' conclusion: The authors concluded that YAP's interaction with TEAD is essential in a Hippo-dependent cancer (mesothelioma) but dispensable in uveal melanoma, and that the usefulness of TEAD inhibitors beyond such cancers may be limited and needs further evaluation
• Limitations the authors state:
  • The authors stated the work relies largely on the dCas9-KRAB (CRISPRi) system and that further studies are needed to confirm YAP's direct contribution
  • The authors stated that further work is needed on what determines where YAP binds in the genome and which complexes it joins

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma.

Related studies

• YAP Activity is Not Associated with Survival of Uveal Melanoma Patients and Cell Lines — Y.J. Kim, S.C. Lee, et al. (2020)
• Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers — E.A. Chapeau, L. Sansregret, et al. (2024)
• Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing — A. Miyanaga, M. Masuda, et al. (2015)
• Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling — J. Wu, A.M. Minikes, et al. (2019)
• The YAP1 Signaling Inhibitors, Verteporfin and CA3, Suppress the Mesothelioma Cancer Stem Cell Phenotype — S. Kandasamy, G. Adhikary, et al. (2020)
• Targeting YAP in malignant pleural mesothelioma — W.Q. Zhang, Y.Y. Dai, et al. (2017)

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