Breast tumor cells promotes the horizontal propagation of EMT, stemness, and metastasis by transferring the MAP17 protein between subsets of neoplastic cells

MAP17 (PDZK1IP1) is a small protein regulating inflammation and tumor progression, upregulated in a broad range of carcinomas. MAP17 levels increase during tumor progression in a large percentage of advanced tumors. In the present work, we explored the role of this protein shaping tumor evolution. Here we show that in breast cancer, cells increased MAP17 levels in tumors by demethylation induced multiple changes in gene expression through specific miRNAs downregulation. These miRNA changes are dependent on Notch pathway activation. As a consequence, epithelial mesenchymal transition (EMT) and stemness are induced promoting the metastatic potential of these cells both in vitro and in vivo. Furthermore, MAP17 increased the exosomes in tumor cells, where MAP17 was released as cargo, and this horizontal propagation also increased the EMT in the recipient cells. Importantly, an antibody against MAP17 in the media reduces the EMT and stemness alterations promoted by the conditioned media from MAP17-expressing cells. Therefore, MAP17 expression promotes the horizontal propagation of EMT and metastasis by transferring the MAP17 protein between subsets of neoplastic cells. Thus, MAP17 can be used to describe a new mechanism for cell malignity at distance, without the involvement of genetic or epigenetic modifications. MAP17 can also be taken in consideration as new target for metastatic high-grade breast tumors.
This work was supported by grants from the Ministerio de Ciencia, Innovación y Universidades (MCIU) Plan Estatal de I+D+I 2018, a la Agencia Estatal de Investigación (AEI) y al Fondo Europeo de Desarrollo Regional (MCIU/AEI/FEDER, UE): RTI2018–097455-B-I00; from AEIMICIU/FEDER (RED2018–102723-T); from CIBER de Cáncer (CB16/12/00275), co-funded by FEDER from Regional Development European Funds (European Union); from Consejería de Salud (PI-0397–2017) and Consejería of Economía, Conocimiento, Empresas y Universidad de Junta de Andalucía (P18-RT-2501). Also especial thanks to the Fundación AECC and Fundación Eugenio Rodriguez Pascual for supporting this work.