cells Review Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling Harriet R. Ferguson 1 , Michael P. Smith 1, * and Chiara Francavilla 1,2, *   Citation: Ferguson, H.R.; Smith, M.P.; Francavilla, C. Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling. Cells 2021, 10, 1201. https://doi.org/10.3390/cells10051201 Academic Editors: Antoni Wiedlocha and Malgorzata Zakrzewska Received: 15 April 2021 Accepted: 9 May 2021 Published: 14 May 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 Division of Molecular and Cellular Function, School of Biological Science, Faculty of Biology Medicine and Health (FBMH), The University of Manchester, Manchester M13 9PT, UK; harriet.ferguson-2@postgrad.manchester.ac.uk 2 Manchester Breast Centre, Manchester Cancer Research Centre, The University of Manchester, Manchester M20 4GJ, UK * Correspondence: michael.smith-8@manchester.ac.uk (M.P.S.); chiara.francavilla@manchester.ac.uk (C.F.) Abstract: Increasing evidence indicates that success of targeted therapies in the treatment of cancer is context-dependent and is influenced by a complex crosstalk between signaling pathways and between cell types in the tumor. The Fibroblast Growth Factor (FGF)/FGF receptor (FGFR) signaling axis highlights the importance of such context-dependent signaling in cancer. Aberrant FGFR signaling has been characterized in almost all cancer types, most commonly non-small cell lung cancer (NSCLC), breast cancer, glioblastoma, prostate cancer and gastrointestinal cancer. This occurs primarily through amplification and over-expression of FGFR1 and FGFR2 resulting in ligand-independent activation. Mutations and translocations of FGFR1-4 are also identified in cancer. Canonical FGF-FGFR signaling is tightly regulated by ligand-receptor combinations as well as direct interactions with the FGFR coreceptors heparan sulfate proteoglycans (HSPGs) and Klotho. Noncanonical FGFR signaling partners have been implicated in differential regulation of FGFR signaling. FGFR directly interacts with cell adhesion molecules (CAMs) and extracellular matrix (ECM) proteins, contributing to invasive and migratory properties of cancer cells, whereas interactions with other receptor tyrosine kinases (RTKs) regulate angiogenic, resistance to therapy, and metastatic potential of cancer cells. The diversity in FGFR signaling partners supports a role for FGFR signaling in cancer, independent of genetic aberration. Keywords: FGFRs; FGFs; signaling; cancer; tumorigenesis; coreceptors; cell adhesion molecules; extracellular matrix; receptor tyrosine kinase; EGFR 1. Introduction The superfamily of Receptor Tyrosine Kinases (RTKs) comprises 20 subfamilies of cell-surface receptors with conserved structures. Upon activation, RTKs undergo dimer- ization, internalization and initiate large-scale tyrosine phosphorylation responses and signaling cascades to regulate cell growth, proliferation, survival and differentiation [1]. The importance of RTKs in cancer was established with the successful introduction of Gleevec, Herceptin and Iressa, the first RTK inhibitors to show antitumor effects approved for clinical use in the early 2000s [2]. In tandem, the role of RTKs in relation to development, tissue homeostasis and other diseases was a growing body of research. Among RTKs, the family of Fibroblast Growth Factor Receptors (FGFRs) comprises four genes that give rise to at least seven different receptor isoforms. These receptors are differentially activated by one of the 22 Fibroblast Growth Factor (FGF) ligands with known FGFR-binding activity, which are nearly ubiquitously expressed in all adult tissues and play a critical role in development, tissue homeostasis and human diseases [3]. Like other RTKs, FGFR1-4 have been implicated in cancers arising from nearly all tissue types [4]. In-line with the number of ligands and receptor variants, FGFR signaling is highly context- specific, which is evidenced by its tumorigenic or tumor suppressor roles in different Cells 2021, 10, 1201. https://doi.org/10.3390/cells10051201 https://www.mdpi.com/journal/cells