Navigator‐3, a modulator of cell migration, may act as a suppressor of breast cancer progression

EMBO Molecular Medicine

Hadas Cohen-Dvashi³  Nir Ben-Chetrit³  Roslin Russell¹  Silvia Carvalho³  Mattia Lauriola³  Sophia Nisani³  Maicol Mancini³  Nishanth Nataraj³  Merav Kedmi³  Lee Roth³  Wolfgang Köstler³  Amit Zeisel⁶  Assif Yitzhaky⁶  Jacques Zylberg⁷  Gabi Tarcic³  Raya Eilam³  Yoav Wigelman³  Rainer Will⁴  Sara Lavi³  Ziv Porat²  Stefan Wiemann⁴  Sara Ricardo⁵  Fernando Schmitt⁵  Carlos Caldas¹ 

[1] Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK;Biological Services, Weizmann Institute of Science, Rehovot, Israel;Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel;Division of Molecular Genome Analysis, German Cancer Research Centre (DKFZ), Heidelberg, Germany;IPATIMUP - Institute of Molecular Pathology and Immunology, Medical Faculty of the University of Porto, Porto, Portugal;Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel;Chemical Physics, Weizmann Institute of Science, Rehovot, Israel

关键词: cancer;    cell migration;    cytoskeleton;    growth factor;    microtubules;   

DOI  :  10.15252/emmm.201404134

来源: Wiley

【 摘 要 】

Abstract

Dissemination of primary tumor cells depends on migratory and invasive attributes. Here, we identify Navigator-3 (NAV3), a gene frequently mutated or deleted in human tumors, as a regulator of epithelial migration and invasion. Following induction by growth factors, NAV3 localizes to the plus ends of microtubules and enhances their polarized growth. Accordingly, NAV3 depletion trimmed microtubule growth, prolonged growth factor signaling, prevented apoptosis and enhanced random cell migration. Mathematical modeling suggested that NAV3-depleted cells acquire an advantage in terms of the way they explore their environment. In animal models, silencing NAV3 increased metastasis, whereas ectopic expression of the wild-type form, unlike expression of two, relatively unstable oncogenic mutants from human tumors, inhibited metastasis. Congruently, analyses of > 2,500 breast and lung cancer patients associated low NAV3 with shorter survival. We propose that NAV3 inhibits breast cancer progression by regulating microtubule dynamics, biasing directionally persistent rather than random migration, and inhibiting locomotion of initiated cells.

Synopsis

A new potential suppressor of metastasis, Navigator-3, acts by modulating migration patterns and conferring a lower probability to locate tissue escape routes.

• Navigator-3 (NAV3), a nerve-navigating gene of worms and a gene frequently mutated or deleted in human tumors, was identified herein as a potential suppressor of metastasis, which associates with good prognosis of breast cancer patients.
• The NAV3 protein localizes to the growing end of microtubules, enhances their growth and augments the ability of cells to adhere to a migration course, while also slowing down migration rates.
• Animal studies indicate that these cellular actions of NAV3 overall reduce the capacity of tumor cells to form metastases, and mathematical modeling attributes this to lower probability to locate rare or transient targets, such as escape routes within tissues.
• NAV3 cancer mutations affect different protein domains; analysis of two point mutants uncovered a destabilization effect, suggesting loss of function in cancer.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.