Tumor Cell Invadopodia: Invasive Protrusions that Orchestrate Metastasis

Invadopodia are a subset of invadosomes that are implicated in the integration of signals from the tumor microenvironment to support tumor cell invasion and dissemination. Recent progress has begun to define how tumor cells regulate the plasticity necessary for invadopodia to assemble and function efficiently in the different microenvironments encountered during dissemination in vivo. Exquisite mapping by many laboratories of the pathways involved in integrating diverse invadopodium initiation signals, from growth factors, to extracellular matrix (ECM) and cell–cell contact in the tumor microenvironment, has led to insight into the molecular basis of this plasticity. Here, we integrate this new information to discuss how the invadopodium is an important conductor that orchestrates tumor cell dissemination during metastasis. Invadopodia form with the same precursor core structure in response to a range of signals from the tumor microenvironment, including soluble growth factors, ECM, cell contact-mediated signaling, and hypoxia. These signals determine tumor phenotype notwithstanding driver mutations initiating the tumor. Different signals lead to invadopodia with different functions in vivo. In addition to their proteolytic function, invadopodia have key roles in sensing the physical properties of the tumor microenvironment, and in the transendothelial migration of tumor cells during dissemination leading to metastasis. In producing localized MMP activity, decreasing stromal pH, and secreting exosomes, invadopodia regulate tumor cell communication over both short and long distances through these modifications of the stromal microenvironment and exosome-mediated establishment of the premetastatic niche.