bims-mesote 2024-10-13 papers

Issue of 2024–10–13
three papers selected by
Laura Mannarino, Humanitas Research

Cureus. 2024 Sep;16(9): e68718

Malignant Mesothelioma: Overcoming Diagnostic Hurdles.

Priya Dharshini R, Sarah Grace Priyadarshini, Jayaganesh P.

Malignant pleural mesothelioma, an aggressive neoplasm frequently linked to asbestos exposure, is often detected at an advanced stage. This report details the case of a 58-year-old mason who presented with left-sided chest pain, and shortness of breath, accompanied by weight loss for a month. A positron emission tomography (PET) scan revealed increased uptake along the pleural surface, as well as in several mediastinal lymph nodes and the left supraclavicular lymph node. Thoracoscopy revealed the presence of multiple nodules on the costal pleura. Despite repeated negative results from pleural effusion cytology, cell block analysis, and pleural biopsies, the diagnosis of malignant mesothelioma (MM) was ultimately established through an ultrasound-guided (USG) biopsy of the left supraclavicular lymph node, with immunohistochemical confirmation using calretinin.

Keywords: asbestos exposure; calretinin positive; malignant pleural mesothelioma (mpm); massive pleural effusion; pleural neoplasm

DOI: https://doi.org/10.7759/cureus.68718

Lung Cancer. 2024 Oct 05. pii: S0169-5002(24)00520-8. [Epub ahead of print]197 107986

Crispr-mediated genome editing reveals a preponderance of non-oncogene addictions as targetable vulnerabilities in pleural mesothelioma.

Duo Xu, Shun-Qing Liang, Min Su, Haitang Yang, Rémy Bruggmann, Simone Oberhaensli, Zhang Yang, Yanyun Gao, Thomas M Marti, Wenxiang Wang, Ralph A Schmid, Yongqian Shu, Patrick Dorn, Ren-Wang Peng.

Pleural mesothelioma (PM) is an aggressive cancer with limited treatment options. In particular, the frequent loss of tumor suppressors, a key oncogenic driver of the disease that is therapeutically intractable, has hampered the development of targeted cancer therapies. Here, we interrogate the PM genome using CRISPR-mediated gene editing to systematically uncover PM cell susceptibilities and provide an evidence-based rationale for targeted cancer drug discovery. This analysis has allowed us to identify with high confidence numerous known and novel gene dependencies that are surprisingly highly enriched for non-oncogenic pathways involved in response to various stress stimuli, in particular DNA damage and transcriptional dysregulation. By integrating genomic analysis with a series of in vitro and in vivo functional studies, we validate and prioritize several non-oncogene addictions conferred by CDK7, CHK1, HDAC3, RAD51, TPX2, and UBA1 as targetable vulnerabilities, revealing previously unappreciated aspects of PM biology. Our findings support the growing consensus that stress-responsive non-oncogenic signaling plays a key role in the initiation and progression of PM and provide a functional blueprint for the development of unprecedented targeted therapies to combat this formidable disease.

Keywords: CRISPR/Cas9; Genetic vulnerability; Non-oncogene addictions; Pleural mesothelioma (PM); Therapeutic targets

DOI: https://doi.org/10.1016/j.lungcan.2024.107986

Cell Rep Med. 2024 Oct 01. pii: S2666-3791(24)00493-2. [Epub ahead of print] 101763

Gene therapy for diffuse pleural mesotheliomas in preclinical models by concurrent expression of NF2 and SuperHippo.

Rui Zhu, Xincheng Liu, Xu Zhang, Zhenxing Zhong, Sixian Qi, Ruxin Jin, Yuan Gu, Yu Wang, Chen Ling, Kang Chen, Dan Ye, Fa-Xing Yu.

Diffuse pleural mesothelioma (DPM) is a lethal cancer with a poor prognosis and limited treatment options. The Hippo signaling pathway genes, such as NF2 and LATS1/2, are frequently mutated in DPM, indicating a tumor suppressor role in the development of DPM. Here, we show that in DPM cell lines lacking NF2 and in mice with a conditional Nf2 knockout, downregulation of WWC proteins, another family of Hippo pathway regulators, accelerates DPM progression. Conversely, the expression of SuperHippo, a WWC-derived minigene, effectively enhances Hippo signaling and suppresses DPM development. Moreover, the adeno-associated virus serotype 6 (AAV6) has been engineered to deliver both NF2 and SuperHippo genes into mesothelial cells, which substantially impedes tumor growth in xenograft and genetic DPM models and prolongs the median survival of mice. These findings serve as a proof of concept for the potential use of gene therapy targeting the Hippo pathway to treat DPM.

Keywords: DPM; Hippo; NF2; WWC proteins; YAP/TAZ; diffuse pleural mesothelioma; gene therapy

DOI: https://doi.org/10.1016/j.xcrm.2024.101763