cells Review Mapping the Metabolic Networks of Tumor Cells and Cancer-Associated Fibroblasts Jessica Karta 1 , Ysaline Bossicard 1 , Konstantinos Kotzamanis 1 , Helmut Dolznig 2 and Elisabeth Letellier 1, *   Citation: Karta, J.; Bossicard, Y.; Kotzamanis, K.; Dolznig, H.; Letellier, E. Mapping the Metabolic Networks of Tumor Cells and Cancer-Associated Fibroblasts. Cells 2021, 10, 304. https://doi.org/10.3390/cells10020304 Academic Editor: Maria Letizia Taddei Received: 16 December 2020 Accepted: 26 January 2021 Published: 2 February 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, 6 avenue du Swing, L-4367 Belval, Luxembourg; jessica.karta@uni.lu (J.K.); ysaline.bossicard@uni.lu (Y.B.); Kostas.Kotzamanis@uni.lu (K.K.) 2 Tumor Stroma Interaction Group, Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, 1090 Vienna, Austria; helmut.dolznig@meduniwien.ac.at * Correspondence: elisabeth.letellier@uni.lu; Tel.: +352-466-644-6954 Abstract: Metabolism is considered to be the core of all cellular activity. Thus, extensive studies of metabolic processes are ongoing in various fields of biology, including cancer research. Cancer cells are known to adapt their metabolism to sustain high proliferation rates and survive in unfavorable environments with low oxygen and nutrient concentrations. Hence, targeting cancer cell metabolism is a promising therapeutic strategy in cancer research. However, cancers consist not only of genetically altered tumor cells but are interwoven with endothelial cells, immune cells and fibroblasts, which together with the extracellular matrix (ECM) constitute the tumor microenvironment (TME). Cancer- associated fibroblasts (CAFs), which are linked to poor prognosis in different cancer types, are one important component of the TME. CAFs play a significant role in reprogramming the metabolic landscape of tumor cells, but how, and in what manner, this interaction takes place remains rather unclear. This review aims to highlight the metabolic landscape of tumor cells and CAFs, including their recently identified subtypes, in different tumor types. In addition, we discuss various in vitro and in vivo metabolic techniques as well as different in silico computational tools that can be used to identify and characterize CAF–tumor cell interactions. Finally, we provide our view on how mapping the complex metabolic networks of stromal-tumor metabolism will help in finding novel metabolic targets for cancer treatment. Keywords: cancer; cancer-associated fibroblasts (CAFs); CAF-tumor cross-talk; tumor metabolism; metabolomics’ measurement techniques; in silico modeling; personalized metabolic drugs 1. Introduction 1.1. CAFs as the Epitome of Tumor Metabolism Max Borst first noted the importance of the tumor microenvironment (TME) on cancer progression in 1902 [1]. Today, it is well acknowledged that the tumor mass includes not only a highly heterogenous cancer cell population but also various types of resident and infiltrating host cells. Cancer-associated fibroblasts (CAFs) are a major component of the TME. CAFs are fibroblasts that display an activated phenotype: they tend to be larger than their normal counterparts, are spindle-shaped and show the presence of stress fibers. This phenotype is transiently observed in normal fibroblasts during wound healing. In contrast, CAFs seem to be constantly activated and unable to revert to a quiescent phenotype [2]. This observation contributed to Harold Dvorak’s definition of cancer as “the wound that does not heal” [3]. Additionally, the CAF genome was reported to be subject to epigenetic reprogramming whereas most studies have not found mutations in CAFs [4]. CAFs communicate with cancer cells in various ways in supporting tumorigenesis. These include signaling molecules, secretion of growth factors, interleukins and metabolite exchanges [5]. CAFs secrete extracellular matrix components such as collagen and laminins, and produce a plethora of cytokines and chemokines (e.g., interferon-γ, stromal cell-derived Cells 2021, 10, 304. https://doi.org/10.3390/cells10020304 https://www.mdpi.com/journal/cells