Hsp27 belongs to the heat shock protein family and displays chaperone properties in stress conditions by holding unfolded polypeptides, hence avoiding their inclination to aggregate. Hsp27 is often referenced as an anti-cancer therapeutic target, but apart from its well-described ability to interfere with different stresses and apoptotic processes, its role in non-stressed conditions is still not well defined. In the present study we report that three polypeptides (histone deacetylase HDAC6, transcription factor STAT2 and procaspase-3) were degraded in human cancerous cells displaying genetically decreased levels of Hsp27. In addition, these proteins interacted with Hsp27 complexes of different native size. Altogether, these findings suggest that HDAC6, STAT2 and procaspase-3 are client proteins of Hsp27. Hence, in non stressed cancerous cells, the structural organization of Hsp27 appears to be a key parameter in the regulation by this chaperone of the level of specific polypeptides through client-chaperone type of interactions.
Background:The small stress heat shock protein 27 (Hsp27) has recently turned as a promising target for cancer treatment. Hsp27 upregulation is associated with tumour growth and resistance to chemo- and radio-therapeutic treatments, and several ongoing drugs inhibiting Hsp27 expression are under clinical trial. Hsp27 is now well described to counteract apoptosis and its elevated expression is associated with increased aggressiveness of several primary tumours. However, its role in the later stage of tumour progression and, more specifically, in the later and most deadly stage of tumour metastasis is still unclear.Methods/results:In the present study, we showed by qRT–PCR that Hsp27 gene is overexpressed in a large fraction of the metastatic breast cancer area in 53 patients. We further analysed the role of this protein in mice during bone metastasis invasion and establishment by using Hsp27 genetically depleted MDA-MB231/B02 human breast cancer cell line as a model. We demonstrate that Hsp27 silencing led to reduced cell migration and invasion in vitro and that in vivo it correlated with a decreased ability of breast cancer cells to metastasise and grow in the skeleton.Conclusion:Altogether, these data characterised Hsp27 as a potent therapeutic target in breast cancer bone metastasis and skeletal tumour growth.
Many reports support that xenografts from patient-derived xenografts (PDXs) in mice or rats well recapitulate the molecular diversity, cellular heterogeneity, and histology seen in patient tumors. However, shortcomings including limited clinical diversity of the PDXs, absence of influence of human microbiome, absence of drug human metabolism and reduced immune system restrain the predictive values of these PDX models. To set-up a holistic integration of these criticisms, we have associated efforts from public hospitals, academic groups, biotechs and private pharmaceutical companies with the financial support of the French Ministry of Industry. First, to improve the clinical cancer diversity, surgical specimens from patients obtained from 8 different tumor locations (lung, breast, ovary, pancreas, liver, prostate, AML, myelome) are collected to establish large collections of PDXs in mice. In addition, in vitro primary cultures of cells from these samples are conducted to establish a collection of cell lines from the stromal and the tumoral compartments. The established models are evaluated for ex vivo and in vivo sensitivities to relevant anticancer drugs, histological and molecular characteristics. All model characteristics are being compiled in a web-based database for efficient features search and interconnection. These tumor collection and model characterization were performed under specific procedures that are followed by all partners within the consortium, which allows to have harmonized results and high quality material. Second, to improve our knowledge on the role of the human gut microbiota, stools are collected from patients with cancer and from mice bearing PDXs before and after chemotherapeutic treatments allowing a comparison of the microbiota profiles. In order to increase the predictability of the models, we are generating mice with humanized liver showing distinct drug pharmacokinetic profiles as compared with parental mice. Finally, the humanization of the immune system in mice is developed by several approaches including the use of induced pluripotent stem cells from cancer patients. We will present the first characterized models and will discuss their usefulness and chance to bring benefit to patients via this holistic strategy developed within the IMODI initiative. Citation Format: Caroline Mignard, Laurent Arnould, Alain Bruno, Loreley Calvet, Marc Colombel, Jill Corre, Olivier Cuvillier, Bénédicte Eckel, Nico Forraz, Alexandra Gonzalez-Jouhanneaud, Liliane Goetsch, Dominique Guenot, Juan Iovanna, Mariana Kuras, Christophe Lautrette, Françoise Le Vacon, Bernard Malavaud, Philippe Merle, Florence Meyer-Losic, Françoise Praz, Olivier Rosmorduc, Jean-Emmanuel Sarry, Séverine Tabone, Philippe Vaglio, Loïc Ysebaert, Olivier Duchamp, IMODI Consortium. Innovative and predictive models against cancer: an IMODI integrative approach. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5203.
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