Understanding the mechanistic features of cancer metastasis

Our efforts to cure cancer patients have led to successful eradication of certain types of primary tumors like breast and prostate cancers. These efforts have also improved the extended delays in metastatic relapses, which can happen decades after treatments of the primary tumors. Unfortunately, once metastases are established, the rate of treatment success drastically decreases. The reason might rely in the fact that the majority of the therapies are generated based on the biology of the primary tumors, which has been the focus of the cancer research field for many decades. In the last 20 years several published evidences have proposed that the origins of metastasis are tumor cells that disseminated from the primary tumors and remained in a dormancy phase resisting therapies for prolonged periods of time. Moreover, pre-malignant cells that disseminated years before the primary tumor developed can undergo dormancy and contribute to metastasis formation. The last scenario is known as parallel progression of the cancer disease and proposes a different evolutionary process in metastasis formation. Thus, therapies that aim to target the heterogeneity present in disseminated tumor cells as well as their origins and behaviors will have greater chances of success. This issue brings together the latest technologies on highresolution microscopy techniques to study tumor-microenvironment interactions, the development of new 3D models that fairly recapitulate the in vivo microenvironments, the dissemination mechanisms involving mitochondria localization and Rho GTPases and our current understanding of tumor dormancy before metastatic outgrowth. The issue opens with a perspective from Katherine O'Brien, a patient advocate who shares her decade long experience as a metastatic breast cancer survivor. She emphasizes that not enough is being done for metastatic patients and there is an immediate need for better support and information system for this group of patients. Chitty et al. describe complex 3D in vitro models to perform rapid screening of potential therapeutic drugs and to test their dissemination capacity. Importantly, the use of these mini-organo models allows the interrogation of the effect of drugs on the stromal compartment. Ju et al. show that the upregulation of a small Rho GTPase, RhoB, under hypoxic conditions may suppress metastasis. This is in agreement with previous work by Fluegen et al. showing that hypoxic conditions within the primary tumor reprogram tumor cells into dormancy delaying their reactivation at secondary organs. Furnish et al. present mounting evidence that cellular localization of mitochondria is crucial for metastatic dissemination of tumor cells. Mayhew et al. describe tumor dormancy in the bone niche with a focus on breast cancer. Lastly, Perrin et al. present a review about the latest applications of intravital multiphoton microscopy in cancer to visualize dynamic interactions between tumor cells and their microenvironments. The knowledge about metastasis biology gathered from these chapters and from ongoing and future investigations in this field will help to develop new therapeutic concepts to ultimately improve the outcomes of cancer patients.