Molecular and Metabolic Reprogramming: Pulling the Strings Toward Tumor Metastasis Ana Hipo ´ lito 1,2† , Filipa Martins 1,2† , Cindy Mendes 1,2† , Filipa Lopes-Coelho 1,2 and Jacinta Serpa 1,2 * 1 CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Cie ˆ ncias Me ´ dicas, Universidade NOVA de Lisboa, Lisboa, Portugal, 2 Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Portugue ˆ s de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisboa, Portugal Metastasis is a major hurdle to the efficient treatment of cancer, accounting for the great majority of cancer-related deaths. Although several studies have disclosed the detailed mechanisms underlying primary tumor formation, the emergence of metastatic disease remains poorly understood. This multistep process encompasses the dissemination of cancer cells to distant organs, followed by their adaptation to foreign microenvironments and establishment in secondary tumors. During the last decades, it was discovered that these events may be favored by particular metabolic patterns, which are dependent on reprogrammed signaling pathways in cancer cells while they acquire metastatic traits. In this review, we present current knowledge of molecular mechanisms that coordinate the crosstalk between metastatic signaling and cellular metabolism. The recent findings involving the contribution of crucial metabolic pathways involved in the bioenergetics and biosynthesis control in metastatic cells are summarized. Finally, we highlight new promising metabolism-based therapeutic strategies as a putative way of impairing metastasis. Keywords: metabolic reprogramming, metastasis, metastatic cascade, tumor microenvironment, new therapies INTRODUCTION Metastasis is the main critical issue in cancer progression, being responsible for 90% of cancer- related deaths (1). The way cancer cells manage to detach from the primary tumor, migrate, invade, and follow the metastatic routes (e.g. hematogenous, lymphatic, serous, direct and nervous) depends on several forces and stresses. The transformation a cancer cell undergoes to get free from the tumor and gain migratory and invasive capacity, requires a multitude of orchestrated molecular changes (2). The most well-known metastatic route is the hematogenous and carcinomas, which account for more than 80% of all the malignant neoplasias, have been the most studied in the metastatic context (3). This metastatic cascade is composed by the following steps: cancer cells release from the primary tumor, local invasion, vessels intravasation, trip on the blood circulation, vessels extravasation, and secondary organs colonization (4)(Figure 1). The epithelial-to-mesenchymal transition (EMT) in cancer cells is an important event to allow these cells to invade and intravasate the vasculature. The morphological alterations necessary for a Frontiers in Oncology | www.frontiersin.org June 2021 | Volume 11 | Article 656851 1 Edited by: Yingying Xu, The First Af filiated Hospital of China Medical University, China Reviewed by: Georg F. Weber, University of Cincinnati, United States Maria Letizia Taddei, University of Florence, Italy *Correspondence: Jacinta Serpa jacinta.serpa@nms.unl.pt † These authors have contributed equally to this work Specialty section: This article was submitted to Cancer Metabolism, a section of the journal Frontiers in Oncology Received: 21 January 2021 Accepted: 11 May 2021 Published: 03 June 2021 Citation: Hipo ´ lito A, Martins F, Mendes C, Lopes-Coelho F and Serpa J (2021) Molecular and Metabolic Reprogramming: Pulling the Strings Toward Tumor Metastasis. Front. Oncol. 11:656851. doi: 10.3389/fonc.2021.656851 REVIEW published: 03 June 2021 doi: 10.3389/fonc.2021.656851