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HSP90 inhibition alters the chemotherapy-driven rearrangement of the oncogenic secretome

Oncogene volume 37, pages 1369–1385 (2018)Cite this article

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Abstract

Adaptive resistance to therapy is a hallmark of cancer progression. To date, it is not entirely clear how microenvironmental stimuli would mediate emergence of therapy-resistant cell subpopulations, although a rearrangement of the cancer cell secretome following therapy-induced stress can be pivotal for such a process. Here, by using the highly chemoresistant malignant pleural mesothelioma (MPM) as an experimental model, we unveiled a key contribution of the chaperone HSP90 at assisting a chemotherapy-instigated Senescence-Associated-Secretory-Phenotype (SASP). Thus, administration of a clinical trial grade, HSP90, inhibitor blunted the release of several cytokines by the chemotherapy-treated MPM cells, including interleukin (IL)-8. Reduction of IL-8 levels hampered the FAK-AKT signaling and inhibited 3D growth and migration. This correlated with downregulation of key EMT and chemoresistance genes and affected the survival of chemoresistant ALDHbright cell subpopulations. Altogether, inhibition of HSP90 provoked a switch from a pro-tumorigenic SASP to a pro-apoptotic senescence status, thus resulting in chemosensitizing effects. In mouse xenografts treated with first-line agents, inhibiting HSP90 blunted FAK activation and reduced the expression of ALDH1A3 and the levels of circulating human IL-8, these latter strongly correlating with the effect on tumor growth. We validated the above findings in primary mesothelioma cultures, a more clinically relevant model. We unveiled here a key contribution of the chaperone HSP90 at assisting the secretory stress in chemotherapy-treated cells, which may warrant further investigation in combinatorial therapeutic settings.

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Fig. 1: HSP90 inhibitors affected viability of malignant pleural mesothelioma (MPM) cells
Fig. 2: Ganetespib treatment turned senescence into apoptosis when co-administered with P + C
Fig. 3: Ganetespib treatment attenuated the protumorigenic properties of the conditioned medium derived from P + C-treated MPM cells
Fig. 4: Ganetespib treatment attenuated the SASP-induced protumorigenic properties in P + C-treated MPM cells
Fig. 5: IL-8 was responsible for the increased pFAK and pAKT following (P + C)-CM addition
Fig. 6: Ganetespib treatment affected tumor growth and resistance to pemetrexed + cisplatin
Fig. 7: Ganetespib addition sensitized primary MPM cultures to P + C

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Acknowledgements

The funding for this study was provided by the Fundacio' La Marato' de TV3 (grant 432/C/2013) to RDM. M.C. was supported by an AIRC and Marie Curie Actions—People—COFUND fellowship. We thankfully acknowledge the support of the Italian Ministry of Health (Progetto Nazionale Amianto) to R.D.M. We thankfully acknowledge the helpful advice of Dr. Paola Nisticò, Dr. Maria Lucia Dell’ Anna, and Dr. Valeria Catena (Regina Elena National Cancer Institute, Rome, Italy).

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Authors and Affiliations

  1. Oncogenomic and Epigenetic Unit Regina Elena National Cancer Institute, Rome, Italy

    Simona di Martino, Giovanni Blandino & Mario Cioce

  2. Department of Pathology Regina Elena National Cancer Institute, Rome, Italy

    Carla Azzurra Amoreo

  3. Preclinical Models and New Therapeutic Agents Unit, Regina Elena National Cancer Institute, Rome, Italy

    Barbara Nuvoli & Rossella Galati

  4. Molecular Chemoprevention Unit, Regina Elena National Cancer Institute, Rome, Italy

    Sabrina Strano

  5. Department of Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy

    Francesco Facciolo & Gabriele Alessandrini

  6. New York University School of Medicine, Department of Cardiothoracic Surgery, New York, NY, USA

    Harvey I. Pass

  7. Scientific Direction, Regina Elena National Cancer Institute, Rome, Italy

    Gennaro Ciliberto & Ruggero De Maria

  8. Current address: Institute of General Pathology, Catholic University and Gemelli Polyclinic, Rome, Italy

    Ruggero De Maria

  9. Department of Oncology, McMaster University, Hamilton, ON, Canada

    Sabrina Strano & Giovanni Blandino

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  1. Simona di Martino
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di Martino, S., Amoreo, C.A., Nuvoli, B. et al. HSP90 inhibition alters the chemotherapy-driven rearrangement of the oncogenic secretome. Oncogene 37, 1369–1385 (2018). https://doi.org/10.1038/s41388-017-0044-8

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