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Heat stress induces epithelial plasticity and cell migration independent of heat shock factor 1

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Cell Stress and Chaperones Aims and scope

Abstract

Current cancer therapies including cytotoxic chemotherapy, radiation and hyperthermic therapy induce acute proteotoxic stress in tumour cells. A major challenge to cancer therapeutic efficacy is the recurrence of therapy-resistant tumours and how to overcome their emergence. The current study examines the concept that tumour cell exposure to acute proteotoxic stress results in the acquisition of a more advanced and aggressive cancer cell phenotype. Specifically, we determined whether heat stress resulted in an epithelial-to-mesenchymal transition (EMT) and/or the enhancement of cell migration, components of an advanced and therapeutically resistant cancer phenotype. We identified that heat stress enhanced cell migration in both the lung A549, and breast MDA-MB-468 human adenocarcinoma cell lines, with A549 cells also undergoing a partial EMT. Moreover, in an in vivo model of thermally ablated liver metastases of the mouse colorectal MoCR cell line, immunohistological analysis of classical EMT markers demonstrated a shift to a more mesenchymal phenotype in the surviving tumour fraction, further demonstrating that thermal stress can induce epithelial plasticity. To identify a mechanism by which thermal stress modulates epithelial plasticity, we examined whether the major transcriptional regulator of the heat shock response, heat shock factor 1 (HSF1), was a required component. Knockdown of HSF1 in the A549 model did not prevent the associated morphological changes or enhanced migratory profile of heat stressed cells. Therefore, this study provides evidence that heat stress significantly impacts upon cancer cell epithelial plasticity and the migratory phenotype independent of HSF1. These findings further our understanding of novel biological downstream effects of heat stress and their potential independence from the classical heat shock pathway.

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Acknowledgments

The authors would like to acknowledge the staff at Monash Micro Imaging and Irene Hatzinisiriou (Monash University) for support in microscopy; staff at Flowcore (Monash University) for FACS support; Brendan Wilding (Monash University) for assistance with software analysis and Ashleigh Unsworth (Monash University) for critical reading of the manuscript. This work was supported by Cancer Council Victoria grant-in-aid no. 545969, National Health and Medical Research Council of Australia R Douglas Wright fellowship no. 395525 (JTP), Australian Postgraduate Award (BJL).

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Lang, B.J., Nguyen, L., Nguyen, H.C. et al. Heat stress induces epithelial plasticity and cell migration independent of heat shock factor 1. Cell Stress and Chaperones 17, 765–778 (2012). https://doi.org/10.1007/s12192-012-0349-z

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