bims-mesote 2023-01-22 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2023‒01‒22
seven papers selected by
Laura Mannarino
Humanitas Research

Serum diagnostic markers for malignant pleural mesothelioma: a narrative review.
Psychosocial well-being among patients with malignant pleural mesothelioma.
BAP1 loss is associated with higher ASS1 expression in epithelioid mesothelioma: implications for therapeutic stratification.
Genomic Instability and Pro-Tumoral Inflammation are associated with Primary Resistance to Anti-PD1 + Anti-Angiogenesis in Malignant Pleural Mesothelioma.
BAP1 is a novel regulator of HIF-1α.
Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma.
Immunohistochemistry for Claudin-4 and BAP1 in the Differential Diagnosis between Sarcomatoid Carcinoma and Sarcomatoid Mesothelioma.

Transl Cancer Res. 2022 Dec;11(12): 4434-4440

Serum diagnostic markers for malignant pleural mesothelioma: a narrative review.

Jing-Jing Wang, Li Yan.

  Background and Objective: The prognosis of patients with malignant pleural mesothelioma (MPM) is poor, and early diagnosis is key to improving the prognosis. Pleural biopsy is the gold reference for diagnosing MPM, but it is an invasive method that can cause operation-related complications such as bleeding and infection. Serum biomarkers, with the advantages of mini-invasiveness, short turnaround time and objectiveness, represent a promising diagnostic tool for MPM.Methods: We searched the PubMed database to identify clinical studies published between 1990 to July 2022 that investigated the diagnostic accuracy of serum biomarkers for MPM. The major findings of the verified studies were summarized.
Key Content and Findings: Currently, there are many available serum markers for MPM, including mesothelin, soluble mesothelin-related peptides, osteopontin, fibulin-3, high mobility group box 1, and microRNA. Systematic review and meta-analysis evidence indicates that the sensitivity and specificity of these serum markers are less than 0.90. In addition, a large portion of previous studies have limitations, especially the representativeness of the study cohort.
Conclusions: The diagnostic accuracy of currently available serum biomarkers is unsatisfactory, and further studies are needed to investigate novel serum biomarkers.

Keywords:  Malignant pleural mesothelioma (MPM); diagnosis; mesothelin; narrative review; osteopontin; serum biomarker

DOI:  https://doi.org/10.21037/tcr-22-2873
Palliat Support Care. 2023 Jan 19. 1-5

Psychosocial well-being among patients with malignant pleural mesothelioma.

Caraline Craig Demirjian, Rebecca M Saracino, Stephanie Napolitano, Elizabeth Schofield, Leah E Walsh, R Garrett Key, Jimmie Holland.

  OBJECTIVES: The investigators conducted a psychosocial needs assessment of mesothelioma patients through self-report measures of quality of life (QOL), coping, depression, and social support.METHODS: Patients with malignant pleural mesothelioma (MPM) (N = 67) completed a battery of assessments at a single timepoint after being approached during routine medical oncology clinic appointments or by letter.
RESULTS: Participants were predominately male (70.0%; n = 47) and ranged in age from 35 to 83 years old (M = 65.61, SD = 9.71). Most participants were white (88.0%; n = 59), and 10.0% (n = 7) were identified as Hispanic. The majority were married or living with a partner (93.0%; n = 62) and had some college or more education (64.0%; n = 43). Fourteen percent of participants (n = 11) endorsed significantly elevated depression symptoms. No significant demographic or clinical differences in depressed compared to nondepressed participants were observed, with a trend toward those identifying as Hispanic and those who were divorced as being more likely to be depressed. For the total sample, the most frequently endorsed coping strategies were active coping, emotional support, and acceptance.
SIGNIFICANCE OF RESULTS: The present study did not identify any clear correlates of depression or QOL among patients with MPM. This research contributes to the small literature on psychosocial functioning in patients with MPM and provides putative directions for future larger studies and the development of interventions to provide appropriate support to diverse patients with MPM.

Keywords:  Coping strategies; Depression; Malignant pleural mesothelioma; Mesothelioma; Needs assessment

DOI:  https://doi.org/10.1017/S1478951522001596
Mol Cancer Res. 2023 Jan 20. pii: MCR-22-0635. [Epub ahead of print]

BAP1 loss is associated with higher ASS1 expression in epithelioid mesothelioma: implications for therapeutic stratification.

Sarah E Barnett, Jenna Kenyani, Martina Tripari, Zohra Butt, Rudi Grosman, Francesca Querques, Liam Shaw, Luisa C Silva, Zoe Goate, Stefan J Marciniak, Doris M Rassl, Richard Jackson, Lu-Yun Lian, Peter W Szlosarek, Joseph J Sacco, Judy M Coulson.

The nuclear deubiquitylase BRCA1 associated protein 1 (BAP1) is frequently inactivated in malignant pleural mesothelioma (MPM) and germline BAP1 mutation predisposes to cancers including MPM. To explore the influence on cell physiology and drug sensitivity, we sequentially edited a predisposition mutation (w-) and a promoter trap (KO) into human mesothelial cells. BAP1w-/KO MeT5A cells express less BAP1 protein and phenocopy key aspects of BAP1 loss in MPM. SILAC-mass spectrometry revealed evidence of metabolic adaptation, with concomitant alteration of cellular metabolites. In MeT5A, BAP1-deficiency reduces glycolytic enzyme levels but increases enzymes involved in the tricarboxylic acid (TCA) cycle and anaplerotic pathways. Notably both argininosuccinate synthase 1 (ASS1), essential for cellular synthesis of arginine, and its substrate aspartate, are elevated in BAP1w-/KO MeT5A cells. Likewise, ASS1 expression is higher in BAP1-altered MPM cell lines, and inversely correlates with BAP1 in the cancer genome atlas (TCGA) MESO dataset. Elevated ASS1 is also evident by immunohistochemical staining in epithelioid MPM lacking nuclear BAP1 expression, with improved survival amongst patients with BAP1-negative/ASS1-expressing tumours. Alterations in arginine metabolism may sensitise cells to metabolic drugs and we find that BAP1-negative/ASS1-expressing MPM cell lines are more sensitive to ASS1 inhibition, although not to inhibition of purine synthesis by mizoribine. Importantly, BAP1w-/KO MeT5A become desensitised to arginine-deprivation by pegylated arginine deiminase (ADI-PEG20), phenocopying BAP1-negative/ASS1-expressing MPM cell lines. Implications: Our data reveal an inter-relationship between BAP1 and arginine metabolism, providing a potential means of identifying epithelioid MPM patients likely to benefit from ADI-PEG20.

DOI: https://doi.org/10.1158/1541-7786.MCR-22-0635
Cancer Discov. 2023 Jan 20. pii: CD-22-0886. [Epub ahead of print]

Genomic Instability and Pro-Tumoral Inflammation are associated with Primary Resistance to Anti-PD1 + Anti-Angiogenesis in Malignant Pleural Mesothelioma.

Francois-Xavier Danlos, Matthieu Texier, Bastien Job, Severine Mouraud, Lydie Cassard, Capucine Baldini, Andrea Varga, Andrey A Yurchenko, Audrey Rabeau, Stephane Champiat, Diane Letourneur, Delphine Bredel, Sandrine Susini, Yuna Blum, Aurelien Parpaleix, Cedric Parlavecchio, Lambros Tselikas, Jean-Eudes Fahrner, Anne-Gaelle Goubet, Mathieu Rouanne, Saloomeh Rafie, Alae Abbassi, Ines Kasraoui, Marie Breckler, Siham Farhane, Samy Ammari, Salim Laghouati, Anas Gazzah, Ludovic Lacroix, Benjamin Besse, Nathalie Droin, Marc Deloger, Sophie Cotteret, Julien Adam, Laurence Zitvogel, Sergey I Nikolaev, Nathalie Chaput, Christophe Massard, Jean-Charles Soria, Carlos Gomez-Roca, Gerard Zalcman, David Planchard, Aurelien Marabelle.

Cancer immunotherapy combinations have recently shown to improve the overall survival of advanced mesotheliomas especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas primary resistance to immunotherapy and anti-angiogenics by testing the combination of pembrolizumab, an anti-PD-1 antibody, and nintedanib, a pan anti-angiogenic tyrosine kinase inhibitor (TKI), in the multi-center PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T-cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy number alterations in their tumors that correlated with high blood and tumor levels of IL-6 and CXCL8. Those pro-inflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T-cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology.

DOI: https://doi.org/10.1158/2159-8290.CD-22-0886
Proc Natl Acad Sci U S A. 2023 Jan 24. 120(4): e2217840120

BAP1 is a novel regulator of HIF-1α.

Angela Bononi, Qian Wang, Alicia A Zolondick, Fang Bai, Mika Steele-Tanji, Joelle S Suarez, Sandra Pastorino, Abigail Sipes, Valentina Signorato, Angelica Ferro, Flavia Novelli, Jin-Hee Kim, Michael Minaai, Yasutaka Takinishi, Laura Pellegrini, Andrea Napolitano, Ronghui Xu, Christine Farrar, Chandra Goparaju, Cristian Bassi, Massimo Negrini, Ian Pagano, Greg Sakamoto, Giovanni Gaudino, Harvey I Pass, José N Onuchic, Haining Yang, Michele Carbone.

  BAP1 is a powerful tumor suppressor gene characterized by haplo insufficiency. Individuals carrying germline BAP1 mutations often develop mesothelioma, an aggressive malignancy of the serosal layers covering the lungs, pericardium, and abdominal cavity. Intriguingly, mesotheliomas developing in carriers of germline BAP1 mutations are less aggressive, and these patients have significantly improved survival. We investigated the apparent paradox of a tumor suppressor gene that, when mutated, causes less aggressive mesotheliomas. We discovered that mesothelioma biopsies with biallelic BAP1 mutations showed loss of nuclear HIF-1α staining. We demonstrated that during hypoxia, BAP1 binds, deubiquitylates, and stabilizes HIF-1α, the master regulator of the hypoxia response and tumor cell invasion. Moreover, primary cells from individuals carrying germline BAP1 mutations and primary cells in which BAP1 was silenced using siRNA had reduced HIF-1α protein levels in hypoxia. Computational modeling and co-immunoprecipitation experiments revealed that mutations of BAP1 residues I675, F678, I679, and L691 -encompassing the C-terminal domain-nuclear localization signal- to A, abolished the interaction with HIF-1α. We found that BAP1 binds to the N-terminal region of HIF-1α, where HIF-1α binds DNA and dimerizes with HIF-1β forming the heterodimeric transactivating complex HIF. Our data identify BAP1 as a key positive regulator of HIF-1α in hypoxia. We propose that the significant reduction of HIF-1α activity in mesothelioma cells carrying biallelic BAP1 mutations, accompanied by the significant reduction of HIF-1α activity in hypoxic tissues containing germline BAP1 mutations, contributes to the reduced aggressiveness and improved survival of mesotheliomas developing in carriers of germline BAP1 mutations.

Keywords:  BAP1; HIF-1α; cancer syndrome; hypoxia; mesothelioma

DOI:  https://doi.org/10.1073/pnas.2217840120
Cell Rep Med. 2023 Jan 10. pii: S2666-3791(22)00494-3. [Epub ahead of print] 100915

Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma.

Gaurav Kumar Pandey, Nick Landman, Hannah K Neikes, Danielle Hulsman, Cor Lieftink, Roderick Beijersbergen, Krishna Kalyan Kolluri, Sam M Janes, Michiel Vermeulen, Jitendra Badhai, Maarten van Lohuizen.

  More than half of patients with malignant mesothelioma show alterations in the BAP1 tumor-suppressor gene. Being a member of the Polycomb repressive deubiquitinating (PR-DUB) complex, BAP1 loss results in an altered epigenome, which may create new vulnerabilities that remain largely unknown. Here, we performed a CRISPR-Cas9 kinome screen in mesothelioma cells that identified two kinases in the mevalonate/cholesterol biosynthesis pathway. Furthermore, our analysis of chromatin, expression, and genetic perturbation data in mesothelioma cells suggests a dependency on PR complex 2 (PRC2)-mediated silencing. Pharmacological inhibition of PRC2 elevates the expression of cholesterol biosynthesis genes only in BAP1-deficient mesothelioma, thereby sensitizing these cells to the combined targeting of PRC2 and the mevalonate pathway. Finally, by subjecting autochthonous Bap1-deficient mesothelioma mice or xenografts to mevalonate pathway inhibition (zoledronic acid) and PRC2 inhibition (tazemetostat), we demonstrate a potent anti-tumor effect, suggesting a targeted combination therapy for Bap1-deficient mesothelioma.

Keywords:  BAP1; EZH2; Polycomb; combination therapy; mesothelioma; mevalonate; preclinical models; targeted therapy; uveal melanoma

DOI:  https://doi.org/10.1016/j.xcrm.2022.100915
Diagnostics (Basel). 2023 Jan 09. pii: 249. [Epub ahead of print]13(2):

Immunohistochemistry for Claudin-4 and BAP1 in the Differential Diagnosis between Sarcomatoid Carcinoma and Sarcomatoid Mesothelioma.

Lina Zuccatosta, Tommaso Bizzarro, Giulio Rossi, Graziana Gallo, Stefano Gasparini, Andrea Ambrosini-Spaltro.

  (1) Background. In the differential diagnosis between sarcomatoid carcinoma (SC) and sarcomatoid mesothelioma (SM), we aimed to investigate the role of Claudin-4 and BAP1, a panel recently used to distinguish conventional carcinoma from epithelioid mesothelioma. (2) Methods. We collected 41 surgical pleural biopsies of SM, 46 surgical resections of SC from different sites and 49 pleural biopsies of normal/hyperplastic mesothelium. All the cases were tested for Claudin-4 and BAP1 using immunohistochemistry. The statistical calculations of the sensitivity, specificity and positive and negative predictive values were performed. (3) Results: Claudin-4 was negative in 41/41 SMs, while it was positive in 18/36 (50.1%) SCs (eight diffusely, 10 focally) within their sarcomatous component. BAP1 was lost in 23/41 SMs, while it was regularly expressed in 46/46 SCs. All the cases of the normal/hyperplastic mesothelium were negative for Claudin-4 and retained the regular expression of BAP1. The Claudin-4 expression was useful for detecting SC (sensitivity, 39.1%; specificity, 100%) and the BAP1 loss was useful for diagnosing SM (sensitivity, 56.1%; specificity, 100%). (4) Conclusions. The staining for Claudin-4 and BAP1 exhibited a low/moderate sensitivity in diagnosing SC and SM (39.1% and 56.1%, respectively), but a very high specificity (100%). Claudin-4 was expressed only in SC and BAP1 loss was noted only in SM.

Keywords:  BAP1; Claudin-4; carcinoma; immunohistochemistry; mesothelioma; pleura; sarcomatoid

DOI:  https://doi.org/10.3390/diagnostics13020249