AHNAK enables mammary carcinoma cells to produce extracellular vesicles that increase neighboring fibroblast cell motility

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// Thaiomara A. Silva 1, * , Basílio Smuczek 1, * , Iuri C. Valadão 1, * , Luciana M. Dzik 1 , Rebeca P. Iglesia 1 , Mário C. Cruz 2 , André Zelanis 3, 4 , Adriane S. de Siqueira 1 , Solange M.T. Serrano 4 , Gary S. Goldberg 5 , Ruy G. Jaeger 1 , Vanessa M. Freitas 1 1 Department of Cell and Developmental Biology, Institute of Biomedical Sciences (ICB), University of Sao Paulo, Sao Paulo, Brazil 2 Center of Facilities and Support Research, Institute of Biomedical Sciences (ICB), Sao Paulo, Brazil 3 Department of Science and Technology, Institute of Science and Technology, Federal University of Sao Paulo (ICT-UNIFESP), Sao Jose dos Campos, Brazil 4 Special Laboratory of Applied Toxinology, Center of Toxins, Immune-Response and Cell Signaling, Butantan Institute, Sao Paulo, Brazil 5 Department of Molecular Biology, School of Osteopathic Medicine, Rowan University, Stratford, New Jersey, USA * These authors have contributed equally to this work Correspondence to: Vanessa M. Freitas, email: vfreitas@usp.br Keywords: extracellular vesicles, cancer, microvesicles, AHNAK, cancer associated fibroblasts Received: October 14, 2015 Accepted: June 12, 2016 Published: June 27, 2016 ABSTRACT Extracellular vesicles play important roles in tumor development. Many components of these structures, including microvesicles and exosomes, have been defined. However, mechanisms by which extracellular vesicles affect tumor progression are not fully understood. Here, we investigated vesicular communication between mammary carcinoma cells and neighboring nontransformed mammary fibroblasts. Nonbiased proteomic analysis found that over 1% of the entire proteome is represented in these vesicles, with the neuroblast differentiation associated protein AHNAK and annexin A2 being the most abundant. In particular, AHNAK was found to be the most prominent component of these vesicles based on peptide number, and appeared necessary for their formation. In addition, we report here that carcinoma cells produce vesicles that promote the migration of recipient fibroblasts. These data suggest that AHNAK enables mammary carcinoma cells to produce and release extracellular vesicles that cause disruption of the stroma by surrounding fibroblasts. This paradigm reveals fundamental mechanisms by which vesicular communication between carcinoma cells and stromal cells can promote cancer progression in the tumor microenvironment.

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