Editorial

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3 pages, 168 KiB

Open AccessEditorial

Managing Malignant Pleural Mesothelioma in the Age of Personalized Medicine: Where Are We and What Is Still Missing?

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Giulia Maria Stella

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Chandra Bortolotto

Cancers 2022, 14(22), 5540; https://doi.org/10.3390/cancers14225540 - 11 Nov 2022

Cited by 1 | Viewed by 968

Abstract

Malignant Mesothelioma (MM) is an aggressive neoplasm of the pleural mesothelium, less frequently peritoneal and exceptionally of the vaginal tunic of the testicle and pericardium [...] Full article

(This article belongs to the Special Issue Malignant Pleural Mesothelioma (MPM))

Research

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19 pages, 2269 KiB

Open AccessArticle

Exploring MicroRNA and Exosome Involvement in Malignant Pleural Mesothelioma Drug Response

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Cancers 2022, 14(19), 4784; https://doi.org/10.3390/cancers14194784 - 30 Sep 2022

Cited by 3 | Viewed by 1795

Abstract

Malignant pleural mesothelioma (MPM) is a deadly thoracic malignancy and existing treatment options are limited. Chemotherapy remains the most widely used first-line treatment regimen for patients with unresectable MPM, but is hampered by drug resistance issues. The current study demonstrated a modest enhancement [...] Read more.

Malignant pleural mesothelioma (MPM) is a deadly thoracic malignancy and existing treatment options are limited. Chemotherapy remains the most widely used first-line treatment regimen for patients with unresectable MPM, but is hampered by drug resistance issues. The current study demonstrated a modest enhancement of MPM cell sensitivity to chemotherapy drug treatment following microRNA (miRNA) transfection in MPM cell lines, albeit not for all tested miRNAs. This effect was more pronounced for FAK (PND-1186) small molecule inhibitor treatment; consistent with previously published data. We previously established that MPM response to survivin (YM155) small molecule inhibitor treatment is unrelated to basal survivin expression. Here, we showed that MPM response to YM155 treatment is enhanced following miRNA transfection of YM155-resistant MPM cells. We determined that YM155-resistant MPM cells secrete a higher level of exosomes in comparison to YM155-sensitive MPM cells. Despite this, an exosome inhibitor (GW4896) did not enhance MPM cell sensitivity to YM155. Additionally, our study showed no evidence of a correlation between the mRNA expression of inhibitor of apoptosis (IAP) gene family members and MPM cell sensitivity to YM155. However, two drug transporter genes, ABCA6 and ABCA10, were upregulated in the MPM cell lines and correlated with poor sensitivity to YM155. Full article

(This article belongs to the Special Issue Malignant Pleural Mesothelioma (MPM))

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23 pages, 3473 KiB

Open AccessArticle

NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma

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Cancers 2021, 13(7), 1561; https://doi.org/10.3390/cancers13071561 - 29 Mar 2021

Cited by 19 | Viewed by 4565

Abstract

(1) Inactivation of the tumor suppressor NF2 is believed to play a major role in the pathogenesis of malignant pleural mesothelioma (MPM) by deregulating the Hippo-YAP signaling pathway. However, NF2 has functions beyond regulation of the Hippo pathway, raising the possibility that NF2 [...] Read more.

(1) Inactivation of the tumor suppressor NF2 is believed to play a major role in the pathogenesis of malignant pleural mesothelioma (MPM) by deregulating the Hippo-YAP signaling pathway. However, NF2 has functions beyond regulation of the Hippo pathway, raising the possibility that NF2 contributes to MPM via Hippo-independent mechanisms. (2) We performed weighted gene co-expression analysis (WGCNA) in transcriptomic and proteomic datasets obtained from The Cancer Gene Atlas (TCGA) MPM cohort to identify clusters of co-expressed genes highly correlated with NF2 and phospho (p)-YAP protein, surrogate markers of active Hippo signaling and YAP inactivation. The potential targets are experimentally validated using a cell viability assay. (3) MPM tumors with NF2 loss-of-function are not associated with changes in p-YAP level nor YAP/TAZ activity score, but are characterized by a deficient B-cell receptor (BCR) signaling pathway. Conversely, MPM tumors with YAP activation display exhausted CD8 T-cell-mediated immunity together with significantly upregulated PD-L1, which is validated in an independent MPM cohort, suggesting a potential benefit of immune-checkpoint inhibitors (ICI) in this patient subset. In support of this, mutations in core Hippo signaling components including LATS2, but not NF2, are independently associated with better overall survival in response to ICI in patients. Additionally, based on cancer cell line models, we show that MPM cells with a high Hippo-YAP activity are particularly sensitive to inhibitors of BCR-ABL/SRC, stratifying a unique MPM patient subset that may benefit from BCR-ABL/SRC therapies. Furthermore, we observe that NF2 physically interacts with a considerable number of proteins that are not involved in the canonical Hippo-YAP pathway, providing a possible explanation for its Hippo-independent role in MPM. Finally, survival analyses show that YAP/TAZ scores together with p-YAP protein level, but not NF2, predict the prognosis of MPM patients. (4) NF2 loss-of-function and dysregulated Hippo-YAP pathway define distinct MPM subsets that differ in their molecular features and prognosis, which has important clinical implications for precision oncology in MPM patients. Full article

(This article belongs to the Special Issue Malignant Pleural Mesothelioma (MPM))

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18 pages, 8445 KiB

Open AccessArticle

C1q–HA Matrix Regulates the Local Synthesis of Hyaluronan in Malignant Pleural Mesothelioma by Modulating HAS3 Expression

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Cancers 2021, 13(3), 416; https://doi.org/10.3390/cancers13030416 - 22 Jan 2021

Cited by 6 | Viewed by 2601

Abstract

Increased hyaluronic acid (HA) production is often associated with cancer progression. In malignant pleural mesothelioma (MPM), HA is found at elevated levels in pleural effusions and sera of patients, and it has been widely debated whether MPM cells are able to produce HA [...] Read more.

Increased hyaluronic acid (HA) production is often associated with cancer progression. In malignant pleural mesothelioma (MPM), HA is found at elevated levels in pleural effusions and sera of patients, and it has been widely debated whether MPM cells are able to produce HA by themselves or through the release of growth factors stimulating other cells. Another key component of the MPM microenvironment is C1q, which can act as a pro-tumorigenic factor favoring cell adhesion, migration and proliferation. The aim of the current study was to prove that MPM primary cells are able to synthesize HA and to inquire the stimulus given by C1q–HA matrix to HA synthesis. We confirmed the presence of a HA coat and cable-like structures around MPM primary cells, as well as an intracellular pool, mainly localized in the cytoplasmic and perinuclear region. After evaluating HA synthase (HAS) enzymes’ basal expression in MPM primary cells, we found that C1q bound to HA was able to impinge upon HA homeostasis by upregulating HAS3 both at the mRNA and the protein levels. High expression of HAS3 has been correlated with a shorter life expectancy in MPM by bioinformatical analysis. These data confirmed that C1q bound to HA may exert pro-tumorigenic activity and identified HAS3 as a potential target in MPM. Full article

(This article belongs to the Special Issue Malignant Pleural Mesothelioma (MPM))

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13 pages, 1927 KiB

Open AccessArticle

Establishment and Characterization of Patient-Derived Xenografts (PDXs) of Different Histology from Malignant Pleural Mesothelioma Patients

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Cancers 2020, 12(12), 3846; https://doi.org/10.3390/cancers12123846 - 20 Dec 2020

Cited by 5 | Viewed by 1858

Abstract

Background: Malignant pleural mesothelioma (MPM) is a very aggressive tumor originating from mesothelial cells. Although several etiological factors were reported to contribute to MPM onset, environmental exposure to asbestos is certainly a major risk factor. The latency between asbestos (or asbestos-like fibers) exposure [...] Read more.

Background: Malignant pleural mesothelioma (MPM) is a very aggressive tumor originating from mesothelial cells. Although several etiological factors were reported to contribute to MPM onset, environmental exposure to asbestos is certainly a major risk factor. The latency between asbestos (or asbestos-like fibers) exposure and MPM onset is very long. MPM continues to be a tumor with poor prognosis despite the introduction of new therapies including immunotherapy. One of the major problems is the low number of preclinical models able to recapitulate the features of human tumors. This impacts the possible discovery of new treatments and combinations. Methods: In this work, we aimed to generate patient-derived xenografts (PDXs) from MPM patients covering the three major histotypes (epithelioid, sarcomatoid, and mixed) occurring in the clinic. To do this, we obtained fresh tumors from biopsies or pleurectomies, and samples were subcutaneously implanted in immunodeficient mice within 24 h. Results: We successfully isolated different PDXs and particularly concentrated our efforts on three covering the three histotypes. The tumors that grew in mice compared well histologically with the tumors of origin, and showed stable growth in mice and a low response to cisplatin, as was observed in the clinic. Conclusions: These models are helpful in testing new drugs and combinations that, if successful, could rapidly translate to the clinical setting. Full article

(This article belongs to the Special Issue Malignant Pleural Mesothelioma (MPM))

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Review

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24 pages, 792 KiB

Open AccessReview

Immunotherapeutic Approaches in Malignant Pleural Mesothelioma

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Cancers 2021, 13(11), 2793; https://doi.org/10.3390/cancers13112793 - 04 Jun 2021

Cited by 8 | Viewed by 2963

Abstract

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignant disease affecting the mesothelium, commonly associated to asbestos exposure. The current therapeutic actions, based on cisplatin/pemetrexed treatment, are limited due to the late stage at which most patients are diagnosed and to the [...] Read more.

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignant disease affecting the mesothelium, commonly associated to asbestos exposure. The current therapeutic actions, based on cisplatin/pemetrexed treatment, are limited due to the late stage at which most patients are diagnosed and to the intrinsic chemo-resistance of the tumor. Another relevant point is the absence of approved therapies in the second line setting following progression of MPM after chemotherapy. Considering the poor prognosis of the disease and the fact that the incidence of this tumor is expected to increase in the next decade, novel therapeutic approaches are urgently needed. In the last few years, several studies have investigated the efficacy and safety of immune-checkpoint inhibitors (ICIs) in the treatment of unresectable advanced MPM, and a number of trials with immunotherapeutic agents are ongoing in both first line and second line settings. In this review, we describe the most promising emerging immunotherapy treatments for MPM (ICIs, engineered T cells to express chimeric antigen receptors (CARs), dendritic cells (DCs) vaccines), focusing on the biological and immunological features of this tumor as well as on the issues surrounding clinical trial design. Full article

(This article belongs to the Special Issue Malignant Pleural Mesothelioma (MPM))

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Other

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22 pages, 1072 KiB

Open AccessSystematic Review

New Updates of the Imaging Role in Diagnosis, Staging, and Response Treatment of Malignant Pleural Mesothelioma

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Chiara Romei

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Salvatore Claudio Fanni

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Federica Volpi

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Alessio Milazzo

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Caterina Aida D’Amore

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Cancers 2021, 13(17), 4377; https://doi.org/10.3390/cancers13174377 - 30 Aug 2021

Cited by 7 | Viewed by 2297

Abstract

Malignant pleural mesothelioma is a rare neoplasm with poor prognosis. CT is the first imaging technique used for diagnosis, staging, and assessment of therapy response. Although, CT has intrinsic limitations due to low soft tissue contrast and the current staging system as well [...] Read more.

Malignant pleural mesothelioma is a rare neoplasm with poor prognosis. CT is the first imaging technique used for diagnosis, staging, and assessment of therapy response. Although, CT has intrinsic limitations due to low soft tissue contrast and the current staging system as well as criteria for evaluating response, it does not consider the complex growth pattern of this tumor. Computer-based methods have proven their potentiality in diagnosis, staging, prognosis, and assessment of therapy response; moreover, computer-based methods can make feasible tasks like segmentation that would otherwise be impracticable. MRI, thanks to its high soft tissue contrast evaluation of contrast enhancement and through diffusion-weighted-images, could replace CT in many clinical settings. Full article

(This article belongs to the Special Issue Malignant Pleural Mesothelioma (MPM))

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13 pages, 13353 KiB

Open AccessOpinion

Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma

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Cancers 2021, 13(13), 3211; https://doi.org/10.3390/cancers13133211 - 27 Jun 2021

Cited by 3 | Viewed by 2247

Abstract

Immunotherapy based on two checkpoint inhibitors (ICI), programmed cell death 1 (PD-1, Nivolumab) and cytotoxic T-lymphocyte 4 (CTLA-4, Ipilimumab), has provided a significant improvement in overall survival for malignant mesothelioma (MM). Despite this major breakthrough, the median overall survival of patients treated with [...] Read more.

Immunotherapy based on two checkpoint inhibitors (ICI), programmed cell death 1 (PD-1, Nivolumab) and cytotoxic T-lymphocyte 4 (CTLA-4, Ipilimumab), has provided a significant improvement in overall survival for malignant mesothelioma (MM). Despite this major breakthrough, the median overall survival of patients treated with the two ICIs only reached 18.1 months vs. 14 months in standard chemotherapy. With an objective response rate of 40%, only a subset of patients benefits from immunotherapy. A critical step in the success of immunotherapy is the presentation of tumor-derived peptides by the major histocompatibility complex I (MHC-I) of tumor cells. These neoantigens are potentially immunogenic and trigger immune responses orchestrated by cytotoxic cells. In MM, tumor development is nevertheless characterized by a low mutation rate despite major structural chromosomal rearrangements driving oncogenesis (BAP1, NF2, CDKN2AB). In this opinion, we propose to investigate an approach based on the mechanisms of the DNA damage tolerance (DDT) pathways to increase the frequency of non-synonymous mutations. The idea is to transiently activate the error-prone DDT in order to generate neoantigens while preserving a fully competent antitumor immune response. Full article

(This article belongs to the Special Issue Malignant Pleural Mesothelioma (MPM))

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