Malignant pleural mesothelioma (MPM) is a rare and incurable cancer, which incidence is increasing in many countries. MPM escapes the classical genetic model of cancer evolution, lacking a distinctive genetic fingerprint. Omics profiling revealed extensive heterogeneity failing to identify major vulnerabilities and restraining development of MPM-oriented therapies. Here, we performed a multilayered analysis based on a functional genome-wide CRISPR/Cas9 screening integrated with patients molecular and clinical data, to identify new non-genetic vulnerabilities of MPM. We identified a core of 18 functionally-related genes as essential for MPM cells. The chromatin reader KAP1 emerged as a dependency of MPM. We showed that KAP1 supports cell growth by orchestrating the expression of a G2/M-specific program, ensuring mitosis correct execution. Targeting KAP1 transcriptional function, by using CDK9 inhibitors resulted in a dramatic loss of MPM cells viability and shutdown of the KAP1-mediated program. Validation analysis on two independent MPM-patients sets, including a consecutive, retrospective cohort of 97 MPM, confirmed KAP1 as new non-genetic dependency of MPM and proved the association of its dependent gene program with reduced patients' survival probability. Overall these data: provided new insights into the biology of MPM delineating KAP1 and its target genes as building blocks of its clinical aggressiveness.

KAP1 is a new non-genetic vulnerability of malignant pleural mesothelioma (MPM) / Lorenzini, Eugenia; Torricelli, Federica; Zamponi, Raffaella; Donati, Benedetta; Manicardi, Veronica; Sauta, Elisabetta; Faria do Valle, Italo; Reggiani, Francesca; Gugnoni, Mila; Manzotti, Gloria; Fragliasso, Valentina; Vitale, Emanuele; Piana, Simonetta; Sancisi, Valentina; Ciarrocchi, Alessia. - In: NAR CANCER. - ISSN 2632-8674. - 4:3(2022), pp. 1-16. [10.1093/narcan/zcac024]

KAP1 is a new non-genetic vulnerability of malignant pleural mesothelioma (MPM)

Torricelli, Federica;Manicardi, Veronica;Manzotti, Gloria;Fragliasso, Valentina;Vitale, Emanuele;Sancisi, Valentina;
2022-01-01

Abstract

Malignant pleural mesothelioma (MPM) is a rare and incurable cancer, which incidence is increasing in many countries. MPM escapes the classical genetic model of cancer evolution, lacking a distinctive genetic fingerprint. Omics profiling revealed extensive heterogeneity failing to identify major vulnerabilities and restraining development of MPM-oriented therapies. Here, we performed a multilayered analysis based on a functional genome-wide CRISPR/Cas9 screening integrated with patients molecular and clinical data, to identify new non-genetic vulnerabilities of MPM. We identified a core of 18 functionally-related genes as essential for MPM cells. The chromatin reader KAP1 emerged as a dependency of MPM. We showed that KAP1 supports cell growth by orchestrating the expression of a G2/M-specific program, ensuring mitosis correct execution. Targeting KAP1 transcriptional function, by using CDK9 inhibitors resulted in a dramatic loss of MPM cells viability and shutdown of the KAP1-mediated program. Validation analysis on two independent MPM-patients sets, including a consecutive, retrospective cohort of 97 MPM, confirmed KAP1 as new non-genetic dependency of MPM and proved the association of its dependent gene program with reduced patients' survival probability. Overall these data: provided new insights into the biology of MPM delineating KAP1 and its target genes as building blocks of its clinical aggressiveness.
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KAP1 is a new non-genetic vulnerability of malignant pleural mesothelioma (MPM) / Lorenzini, Eugenia; Torricelli, Federica; Zamponi, Raffaella; Donati, Benedetta; Manicardi, Veronica; Sauta, Elisabetta; Faria do Valle, Italo; Reggiani, Francesca; Gugnoni, Mila; Manzotti, Gloria; Fragliasso, Valentina; Vitale, Emanuele; Piana, Simonetta; Sancisi, Valentina; Ciarrocchi, Alessia. - In: NAR CANCER. - ISSN 2632-8674. - 4:3(2022), pp. 1-16. [10.1093/narcan/zcac024]
Lorenzini, Eugenia; Torricelli, Federica; Zamponi, Raffaella; Donati, Benedetta; Manicardi, Veronica; Sauta, Elisabetta; Faria do Valle, Italo; Reggiani, Francesca; Gugnoni, Mila; Manzotti, Gloria; Fragliasso, Valentina; Vitale, Emanuele; Piana, Simonetta; Sancisi, Valentina; Ciarrocchi, Alessia
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1290329
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