title: Deciphering Cell-to-Cell Communication in Acquisition of Cancer Traits: Extracellular Membrane Vesicles Are Regulators of Tissue Biomechanics.
abstract: Deciphering the role of cell-to-cell communication in acquisition of cancer traits such as metastasis is one of the key challenges of integrative biology and clinical oncology. In this context, extracellular vesicles (EVs) are important vectors in cell-to-cell communication and serve as conduits in the transfer of cellular constituents required for cell function and for the establishment of cellular phenotypes. In the case of malignancy, they have been shown to support the acquisition of common traits defined as constituting the hallmarks of cancer. Cellular biophysics has contributed to our understanding of some of these central traits with changes in tissue biomechanics reflective of cell state. Indeed, much is known about stiffness of the tissue scaffold in the context of cell invasion and migration. This article advances this knowledge frontier by showing for the first time that EVs are mediators of tissue biomechanical properties and, importantly, demonstrates a link between the acquisition of cancer multidrug resistance and increased tissue stiffness of the malignant mass. The methodology used in the study employed optical coherence elastography and atomic force microscopy on breast cancer cell monolayers and tumor spheroids. Specifically, we show here that the acquired changes in tissue stiffness can be attributed to the intracellular transfer of a protein complex comprising ezrin, radixin, moesin, CD44, and P-glycoprotein. This has important implications in facilitating mechano-transduced signaling cascades that regulate the acquisition of cancer traits, such as invasion and metastasis. Finally, this study also introduces novel targets and strategies for diagnostic and therapeutic innovation in oncology, with a view to prevention of metastatic spread and personalized medicine in cancer treatment.
authors: 1 Discipline of Pharmacy, The Graduate School of Health, University of Technology Sydney , Australia .
authors: Deep
authors: D
authors: Pokharel
authors: 2 Optical+Biomedical Engineering Laboratory, School of Electrical, Electronic and Computer Engineering, The University of Western Australia , Western Australia, Australia .
authors: Philip
authors: P
authors: Wijesinghe
authors: 1 Discipline of Pharmacy, The Graduate School of Health, University of Technology Sydney , Australia .
authors: Vici
authors: V
authors: Oenarto
authors: 1 Discipline of Pharmacy, The Graduate School of Health, University of Technology Sydney , Australia .
authors: Jamie F
authors: JF
authors: Lu
authors: 2 Optical+Biomedical Engineering Laboratory, School of Electrical, Electronic and Computer Engineering, The University of Western Australia , Western Australia, Australia .|3 Centre for Microscopy, Characterisation and Analysis, The University of Western Australia , Western Australia, Australia .
authors: David D
authors: DD
authors: Sampson
authors: 2 Optical+Biomedical Engineering Laboratory, School of Electrical, Electronic and Computer Engineering, The University of Western Australia , Western Australia, Australia .|4 BRITElab, Harry Perkins Institute of Medical Research , Western Australia, Australia .
authors: Brendan F
authors: BF
authors: Kennedy
authors: 5 School of Physics, The University of Western Australia , Western Australia, Australia .
authors: Vincent P
authors: VP
authors: Wallace
authors: 1 Discipline of Pharmacy, The Graduate School of Health, University of Technology Sydney , Australia .
authors: Mary
authors: M
authors: Bebawy
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D001696:Biomechanical Phenomena; D002450:Cell Communication / Q000235:genetics*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000235:genetics; D000067128:Extracellular Vesicles / Q000235:genetics*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D010641:Phenotype; D057285:Precision Medicine; D015398:Signal Transduction; D000099149:Ezrin
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D003598:Cytoskeletal Proteins; D018960:Hyaluronan Receptors; D008565:Membrane Proteins; D008840:Microfilament Proteins; D000099149:Ezrin; C497483:CD44 protein, human; C071058:moesin; C071776:radixin