bims-mesote 2023-07-09 papers

Issue of 2023–07–09
four papers selected by
Laura Mannarino, Humanitas Research

Front Immunol. 2023 ;14 1116430

Important functional role of the protein osteopontin in the progression of malignant pleural mesothelioma.

Elisabeth Digifico, Marco Erreni, Laura Mannarino, Sergio Marchini, Aldo Ummarino, Clément Anfray, Luca Bertola, Camilla Recordati, Daniela Pistillo, Massimo Roncalli, Paola Bossi, Paolo Andrea Zucali, Maurizio D'Incalci, Cristina Belgiovine, Paola Allavena.

Background: Malignant Pleural Mesothelioma (MPM) is an aggressive cancer of the mesothelial lining associated with exposure to airborne non-degradable asbestos fibers. Its poor response to currently available treatments prompted us to explore the biological mechanisms involved in its progression. MPM is characterized by chronic non-resolving inflammation; in this study we investigated which inflammatory mediators are mostly expressed in biological tumor samples from MPM patients, with a focus on inflammatory cytokines, chemokines and matrix components.
Methods: Expression and quantification of Osteopontin (OPN) was detected in tumor and plasma samples of MPM patients by mRNA, immunohistochemistry and ELISA. The functional role of OPN was investigated in mouse MPM cell lines in vivo using an orthotopic syngeneic mouse model.
Results: In patients with MPM, the protein OPN was significantly more expressed in tumors than in normal pleural tissues and predominantly produced by mesothelioma cells; plasma levels were elevated in patients and associated with poor prognosis. However, modulation of OPN levels was not significantly different in a series of 18 MPM patients receiving immunotherapy with durvalumab alone or with pembrolizumab in combination with chemotherapy, some of whom achieved a partial clinical response. Two established murine mesothelioma cell lines: AB1 and AB22 of sarcomatoid and epithelioid histology, respectively, spontaneously produced high levels of OPN. Silencing of the OPN gene (Spp1) dramatically inhibited tumor growth in vivo in an orthotopic model, indicating that OPN has an important promoting role in the proliferation of MPM cells. Treatment of mice with anti-CD44 mAb, blocking a major OPN receptor, significantly reduced tumor growth in vivo.
Conclusion: These results demonstrate that OPN is an endogenous growth factor for mesothelial cells and inhibition of its signaling may be helpful to restrain tumor progression in vivo. These findings have translational potential to improve the therapeutic response of human MPM.

Keywords: MPM (malignant pleural mesothelioma); immune system and cancer; immunotherapy; novel therapeutic approach; osteopontin (OPN)

DOI: https://doi.org/10.3389/fimmu.2023.1116430

Lung Cancer. 2023 Jun 26. pii: S0169-5002(23)00825-5. [Epub ahead of print]182 107287

VEGFR2 and CD34 expression associated with longer survival in patients with pleural mesothelioma in the IFCT-GFPC-0701 MAPS phase 3 trial.

Guénaëlle Levallet, Fatéméh Dubois, Nicolas Elie, Christian Creveuil, Solenn Brosseau, Claire Danel, Arnaud Scherpereel, Sylvie Lantuejoul, Julien Mazières, Laurent Greillier, Clarisse Audigier-Valette, Emmanuel Bergot, Denis Moro-Sibilot, Olivier Molinier, Hervé Léna, Isabelle Monnet, Franck Morin, Valérie Gounant, Gérard Zalcman.

OBJECTIVES: VEGF/VEGFR autocrine loop is a hallmark of pleural mesothelioma (PM). We thus assayed the prognostic and predictive values of VEGFR-2 [vascular endothelial growth factor receptor 2 or Flk-1] and CD34, a marker of endothelial cells, in samples from patients accrued in the Mesothelioma Avastin Cisplatin Pemetrexed Study ('MAPS', NCT00651456).
MATERIALS AND METHODS: VEGFR2 and CD34 expression were assayed using immunohistochemistry in 333 MAPS patients (74.3%), and their prognostic value was evaluated in terms of overall survival (OS) and progression-free survival (PFS) in univariate and multivariate analyses, before validation by bootstrap methodology.
RESULTS: Positive VEGFR2 or CD34 staining was observed in 234/333 (70.2%) and 322/323 (99.6%) of tested specimens, respectively. VEGFR2 and CD34 staining correlated weakly, yet significantly, with each other (r = 0.36, p < 0.001). High VEGFR2 expression or high CD34 levels were associated with longer OS in PM patients in multivariate analysis (VEGFR2: adjusted [adj.] hazard ratio [HR]: 0.91, 95% confidence interval [CI] [0.88; 0.95], p < 0.001; CD34: adj. HR: 0.86, 95 %CI [0.76; 0.96], p = 0.010), with only high VEGFR2 expression resulting in significantly longer PFS (VEGFR2: adj. HR: 0.96, 95 %CI [0.92; 0.996], p = 0.032). Stability of these results was confirmed using bootstrap procedure. Nevertheless, VEGFR2 expression failed to specifically predict longer survival in bevacizumab-chemotherapy combination trial arm, regardless of whether the VEGFR2 score was combined or not with serum VEGF concentrations.
CONCLUSION: VEGFR2 overexpression independently correlated with longer OS or PFS in PM patients, such biomarker deserving prospective evaluation as stratification variable in future clinical trials.

Keywords: Bevacizumab; CD34; Malignant pleural mesothelioma; Neo-angiogenesis; VEGFR2

DOI: https://doi.org/10.1016/j.lungcan.2023.107287

Biochem Pharmacol. 2023 Jul 01. pii: S0006-2952(23)00269-1. [Epub ahead of print]214 115678

Mesenchymal stromal cells loaded with Paclitaxel (PacliMES) a potential new therapeutic approach on mesothelioma.

Valentina Coccè, Mara Bonelli, Silvia La Monica, Roberta Alfieri, Luisa Doneda, Eleonora Martegani, Giulio Alessandri, Costanza Annamaria Lagrasta, Aldo Giannì, Valeria Sordi, Francesco Petrella, Leda Roncoroni, Francesca Paino, Augusto Pessina.

Malignant pleural mesothelioma is an asbestos-related tumor originating in mesothelial cells of the pleura that poorly responds to chemotherapeutic approaches. Adult mesenchymal stromal cells derived either from bone marrow or from adipose tissue may be considered a good model for cell-based therapy, a treatment which has experienced significant interest in recent years. The present study confirms that Paclitaxel is effective on mesothelioma cell proliferation in 2D and 3D in vitro cultures, and that 80,000 mesenchymal stromal cells loaded with Paclitaxel inhibit tumor growth at a higher extent than Paclitaxel alone. An in vivo approach to treat in situ mesothelioma xenografts using a minimal amount of 106 mesenchymal stromal cells loaded with Paclitaxel showed the same efficacy of a systemic administration of 10 mg/kg of Paclitaxel. These data strongly support drug delivery system by mesenchymal stromal cells as a useful approach against many solid tumors. We look with interest at the favourable opinion recently expressed by the Italian Drug Agency on the procedure for the preparation of mesenchymal stromal cells loaded with Paclitaxel in large-scale bioreactor systems and their storage until clinical use. This new Advanced Medicinal Therapy Product, already approved for a Phase I clinical trial on mesothelioma patients, could pave the way for mesenchymal stromal cells use as drug delivery system on other solid tumors for adjuvant therapy associated with surgery and radiotherapy.

Keywords: Drug delivery; Mesenchymal stem cells (MSCs); Mesothelioma; Paclitaxel

DOI: https://doi.org/10.1016/j.bcp.2023.115678

Nat Commun. 2023 07 03. 14(1): 3907

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

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.

DOI: https://doi.org/10.1038/s41467-023-39527-w