Teneurins: An Integrative Molecular, Functional, and Biomedical Overview of Their Role in Cancer

Abstract

Teneurins are large transmembrane proteins originally identified in Drosophila. Their essential role in development of the central nervous system is conserved throughout species, and evidence supports their involvement in organogenesis of additional tissues. Homophilic and heterophilic interactions between Teneurin paralogues mediate cellular adhesion in crucial processes such as neuronal pathfinding and synaptic organization. At the molecular level, Teneurins are proteolytically processed into distinct subdomains that have been implicated in extracellular and intracellular signaling, and in transcriptional regulation. Phylogenetic studies have shown a high degree of intra- and interspecies conservation of Teneurin genes. Accordingly, the occurrence of genetic variants has been associated with functional and phenotypic alterations in experimental systems, and with some inherited or sporadic conditions. Recently, tumor-related variations in Teneurin gene expression have been associated with patient survival in different cancers. Although these findings were incidental and molecular mechanisms were not addressed, they suggested a potential utility of Teneurin transcript levels as biomarkers for disease prognosis. Mutations and chromosomal alterations affecting Teneurin genes have been found occasionally in tumors, but literature remains scarce. The analysis of open-access molecular and clinical datasets derived from large oncologic cohorts provides an invaluable resource for the identification of additional somatic mutations. However, Teneurin variants have not been classified in terms of pathogenic risk and their phenotypic impact remains unknown. On this basis, is it plausible to hypothesize that Teneurins play a role in carcinogenesis? Does current evidence support a tumor suppressive or rather oncogenic function for these proteins? Here, we comprehensively discuss available literature with integration of molecular evidence retrieved from open-access databases. We show that Teneurins undergo somatic changes comparable to those of well-established cancer genes, and discuss their involvement in cancer-related signaling pathways. Current data strongly suggest a functional contribution of Teneurins to human carcinogenesis.

Identification of TENM4 as a Novel Cancer Stem Cell-Associated Molecule and Potential Target in Triple Negative Breast Cancer

“…Besides their predominant neural distribution, teneurins mRNA have been detected in few adult organs such as the testis and thymus although at significantly lower levels [ 62 ]. Current data support the aberrant expression of teneurins in tumors of different histotypes, their involvement in cancer-related regulatory networks, their possible contribution in drug resistance [ 25 ], and their association with cancer patients’ survival [ 23 ]. However, data available from the literature reveals that the association between teneurins expression and patients’ prognosis is not univocal since it depends on the type of teneurin and on the tumor histotype [ 23 ].…”

“…TENM4 expression increases from epithelial cells to tumorspheres, providing them advantages in self-renewal and migration ability. Beside its well described role in organogenesis [ 20 ] and in the development of the nervous system [ 21 , 22 ], TENM4 has been recently liked with cancer where its deregulated expression correlates with patients’ prognosis [ 23 , 24 ]. Moreover, the protein family of teneurins seems to have a role in tumorigenesis thanks to the ability of its members, including TENM4, to modulate cell differentiation [ 23 , 25 ].…”

Somatic Genetic Aberrations in Benign Breast Disease and the Risk of Subsequent Breast Cancer

“…TENM4 is one of four highly related human teneurin paralogues 61 . The teneurins are large transmembrane glycoproteins with many structural similarities to Notch which include their analogous transmembrane localization, their capability to dimerize upon ligand interaction, the presence of multiple epidermal growth factor-like (EGF) repeats in their extracellular domains, and their processing into multiple domains through proteolytic cleavage 62 . A catalog of chromosomal translocations involving the teneruins discovered that 18/32 (56%) of these occurred in breast cancer (16 of which involved TENM4), and most were intrachromosomal (22/32, 69%) 62 .…”

NRG1 fusions in breast cancer

“…[9]). TENM4, teneurin4, has been identified as a probable driver target of structural variation, notably in the breast [37] and Fig. 3b of ref.…”