Genomic and transcriptomic analyses identify a prognostic gene signature and predict response to therapy in pleural and peritoneal mesothelioma

Nair, Nishanth Ulhas; Jiang, Qun; Wei, Jun S.; Misra, Vikram; Morrow, Betsy; Kesserwan, Chimene; Hermida, Leandro; Lee, Joo Sang; Mian, Idrees; Zhang, Jingli; Lebensohn, Alexandra; Miettinen, Markku; Sengupta, Manjistha; Khan, Javed; Ruppin, Eytan; Hassan, Raffit

doi:10.1016/j.xcrm.2023.100938

Cited by 11 publications

(9 citation statements)

References 67 publications

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“…7B ). Moreover, in the entire 100 NCI human MM RNA-seq dataset ( 16 ), CD163 mRNA expression showed a highly significant positive correlation with multiple genes encoding proteins involved in the CD39/CD73–adenosine, CCR2, and other immunosuppressive pathways, that is, IL10 , IL10RA , MRC1 (CD206), and STAT3 ( Fig. 7C ), forming an interconnected network consistent with our mouse data.…”

Section: Resultssupporting

confidence: 82%

“…To assess the clinical relevance of our mouse model findings, we analyzed NCI human MM RNA-seq data ( n = 100) and germline variants data ( 16 ). We examined clinical and pathologic aspects of sporadic MMs and MM tumors from patients with germline BAP1 mutations ( n = 11), investigating gene expression correlations between genes related to M1/M2 macrophages and other immune signatures outlined in our investigation.…”

Section: Resultsmentioning

confidence: 99%

“… Preliminary clinical connections of mouse findings based on NCI human MM RNA-seq and germline mutation data ( 16 ). A, Comparison of CCL2 mRNA expression levels based on BAP1 germline mutation status in 100 MM samples from the NCI cohort.…”

Section: Resultsmentioning

confidence: 99%

“…We downloaded MM normalized RNA sequencing (RNA-seq; n = 100), germline mutation status, and clinical data from Supplementary Tables S1 , S3, and S4 of the NCI report by Nair and colleagues ( 16 ). The RNA-seq data were normalized using trimmed mean of M-values, and log counts per million transformed using edgeR ( 17 ).…”

Section: Methodsmentioning

confidence: 99%

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Low Exposures to Amphibole or Serpentine Asbestos in Germline Bap1-mutant Mice Induce Mesothelioma Characterized by an Immunosuppressive Tumor Microenvironment

Kadariya,

Sementino,

Ruan

et al. 2024

Cancer Research Communications

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Asbestos and BAP1 germline mutations are risk factors for malignant mesothelioma (MM). While it is well accepted that amphibole asbestos is carcinogenic, the role of serpentine (chrysotile) asbestos in MM has been debated. To address this controversy, we assessed whether minimal exposure to chrysotile could significantly increase the incidence and rate of MM onset in germline Bap1-mutant mice. With either crocidolite or chrysotile, and at each dose tested, MMs occurred at a significantly higher rate and earlier onset time in Bap1-mutant mice than in wild-type littermates. To explore the role of gene–environment interactions in MMs from Bap1-mutant mice, we investigated proinflammatory and protumorigenic factors and the tumor immune microenvironment (TIME). IHC and immunofluorescence staining showed an increased number of macrophages in granulomatous lesions and MMs. The relative number of CD163-positive (CD163+) M2 macrophages in chrysotile-induced MMs was consistently greater than in crocidolite-induced MMs, suggesting that chrysotile induces a more profound immunosuppressive response that creates favorable conditions for evading immune surveillance. MMs from Bap1-mutant mice showed upregulation of CD39/CD73-adenosine and C-C motif chemokine ligand 2 (Ccl2)/C-C motif chemokine receptor 2 (Ccr2) pathways, which together with upregulation of IL6 and IL10, promoted an immunosuppressive TIME, partly by attracting M2 macrophages. Interrogation of published human MM RNA sequencing (RNA-seq) data implicated these same immunosuppressive pathways and connections with CD163+ M2 macrophages. These findings indicate that increased M2 macrophages, along with upregulated CD39/CD73-adenosine and Ccl2/Ccr2 pathways, contribute to an immunosuppressive TIME in chrysotile-induced MMs of Bap1-mutant mice, suggesting that immunotherapeutic strategies targeting protumorigenic immune pathways could be beneficial in human BAP1 mutation carriers who develop MM. Significance: We show that germline Bap1-mutant mice have enhanced susceptibility to MM upon minimal exposure to chrysotile asbestos, not only amphibole fibers. Chrysotile induced a more profound immune tumor response than crocidolite in Bap1-mutant mice by upregulating CD39/CD73-adenosine and Ccl2/Ccr2 pathways and recruiting more M2 macrophages, which together contributed to an immunosuppressive tumor microenvironment. Interrogation of human MM RNA-seq data revealed interconnected immunosuppressive pathways consistent with our mouse findings.

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Section: Resultssupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Low Exposures to Amphibole or Serpentine Asbestos in Germline Bap1-mutant Mice Induce Mesothelioma Characterized by an Immunosuppressive Tumor Microenvironment

Kadariya,

Sementino,

Ruan

et al. 2024

Cancer Research Communications

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“…MPM and MPeM have similarities of cellular features and common genetic alterations. The genomic profile of MM reveals a low protein-coding mutation rate, with the most commonly occurring alterations being mutations and deletions of the tumor suppressor genes (TSGs) BRCA1 associated protein-1 (BAP1; located at chromosome band 3p21), neurofibromatosis type 2 (NF2; 22q12), and cyclin-dependent kinase inhibitor 2A and 2B (CDKN2A/B; 9p21) [9][10][11][12][13][14] . Recently, we provided a comprehensive analysis of data on MPM tumors with genomic alteration in one or more of these specific TSGs, which are thought to be critical drivers of MPM pathogenesis 15 .…”

Section: Introductionmentioning

confidence: 99%

Spatial landscape of malignant pleural and peritoneal mesothelioma tumor immune microenvironment

Ma,

Lembersky,

Kim

et al. 2023

Preprint

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Immunotherapies have shown modest clinical benefit thus far for malignant mesothelioma (MM). A deeper understanding of immune cell spatial distribution within the tumor immune microenvironment (TIME) is needed to identify interactions between tumor and different immune cell types that might impact the effectiveness of potential immunotherapies. We performed multiplex immunofluorescence (mIF) using tissue microarrays (TMAs, n=3) of samples from patients with malignant peritoneal (n=25) and pleural (n=88) mesothelioma (MPeM and MPM, respectively) to elucidate the spatial distributions of major immune cell populations and their association with LAG3, BAP1, NF2, and MTAP expression, the latter as a proxy for CDKN2A/B. We also analyzed the relationship between the spatial distribution of major immune cell types with MM patient prognosis and clinical features. The distribution of immune cells within the TIME is similar between MPM and MPeM. However, there is a higher level of interaction between immune cells and tumor cells in MPM than MPeM. Within MPM tumors, there is increased amount of interaction between tumor cells and CD8+ T cells in BAP1-low than in BAP1-high expressing tumors. The cell-cell interactions identified in this investigation have potential implications for the immune response against MM tumors and could be a factor in the different behaviors of MPM and MPeM. Our findings provide a valuable resource for the MM cancer research community and exemplifies the utility of spatial resolution within single-cell analyses. Our mesothelioma spatial atlas mIF dataset is available at https://mesotheliomaspatialatlas.streamlit.app/.

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Genomic Landscape of Pleural Mesothelioma and Therapeutic Aftermaths

Nash,

Creaney

2023

Curr Oncol Rep

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Purpose of Review In this article, we provide a comprehensive analysis of recent progress in the genetic characterisation of pleural mesothelioma, and the translation of these findings to clinical practice. Recent Findings Advancements in sequencing technology have allowed the identification of driver mutations and improved our understanding of how these mutations may shape the mesothelioma tumour microenvironment. However, the identification of frequently mutated regions including CDKN2A, BAP1 and NF2 have, to date, not yet yielded targeted therapy options that outperform standard chemo- and immunotherapies. Similarly, the association between mutational profile and the immune microenvironment or immunotherapy response is not well characterised. Summary Further research into the link between tumour mutational profile and response to therapy is critical for identifying targetable vulnerabilities and stratifying patients for therapy.

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Genomic and transcriptomic analyses identify a prognostic gene signature and predict response to therapy in pleural and peritoneal mesothelioma

Cited by 11 publications

References 67 publications

Low Exposures to Amphibole or Serpentine Asbestos in Germline Bap1-mutant Mice Induce Mesothelioma Characterized by an Immunosuppressive Tumor Microenvironment

Low Exposures to Amphibole or Serpentine Asbestos in Germline Bap1-mutant Mice Induce Mesothelioma Characterized by an Immunosuppressive Tumor Microenvironment

Spatial landscape of malignant pleural and peritoneal mesothelioma tumor immune microenvironment

Genomic Landscape of Pleural Mesothelioma and Therapeutic Aftermaths

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