Expression of teneurins is associated with tumor differentiation and patient survival in ovarian cancer

Abstract

Teneurins are a family of highly conserved pair-rule proteins involved in morphogenesis and development of the central nervous system. Their function in adult tissues and in disease is largely unknown. Recent evidence suggests a role for dysregulated expression of Teneurins in human tumors, but systematic investigations are missing. Here, we investigated Teneurin-2 and Teneurin-4 expression in various cancer cell lines and in ovarian tumor tissues. Teneurin-2 and Teneurin-4 were expressed in most of the breast cancer cell lines tested. Teneurin-4 was also detected in ovarian cancer cell lines, and throughout ovarian tumors and normal ovary tissue. Ovarian tumors with low Teneurin-4 expression showed less differentiated phenotypes and these patients had shorter mean overall survival. Similarly, Teneurin-2 expression correlated with overall survival as well, especially in patients with serous tumors. In the various cell lines, 5-Aza-cytidine-induced changes in DNA methylation did not alter expression of Teneurin-2 and Teneurin-4, despite the existence of predicted CpG islands in both genes. Interestingly, however, we found evidence for the control of Teneurin-2 expression by the oncogenic growth factor FGF8. Furthermore, we identified multiple transcript splicing variants for Teneurin-2 and Teneurin-4, indicating complex gene expression patterns in malignant cells. Finally, downregulation of Teneurin-4 expression using siRNA caused a cell-type dependent increase in proliferation and resistance to cisplatin. Altogether, our data suggest that low Teneurin-4 expression provides a growth advantage to cancer cells and marks an undifferentiated state characterized by increased drug resistance and clinical aggressiveness. We conclude that Teneurin-2 and Teneurin-4 expression levels could be of prognostic value in ovarian cancer.

Alternative splicing controls teneurin-latrophilin interaction and synapse specificity by a shape-shifting mechanism

“…1c) [7][8][9] . TENs have central roles in tissue polarity, embryogenesis, heart development, axon guidance, and synapse formation 6,[10][11][12][13][14][15][16][17] ; and are linked to various diseases including neurological disorders, developmental problems, various cancers, and congenital general anosmia [18][19][20][21][22][23][24] . LPHNs (LPHN1-3 in mammals) belong to the adhesion-type G-protein coupled receptor (GPCR) family [25][26][27] and have a large N-terminal ECR (>800 amino acids) in addition to their signaling seven-pass transmembrane domain and cytoplasmic tail (Fig.…”

Cell Line-, Protein-, and Sialoglycosite-Specific Control of Flux-Based Sialylation in Human Breast Cells: Implications for Cancer Progression

“…Third, TENM3 (Teneurin-3) is a single pass, richly glycosylated type II transmembrane protein that is one of four human Teneurins, a family involved in cell-cell adhesion and organization of neuronal synapses (Mosca, 2015;Jackson et al, 2018). Teneurins 2 and 4 have been linked to tumor differentiation and patient survival in ovarian cancer (Graumann et al, 2017) and Teneurin 3 is expressed at low to moderate levels in a subset of breast cancer patients (e.g., 4 of 12 reported in the Protein Atlas database, https://www.proteinatlas. org/ENSG00000218336-TENM3/pathology).…”

Structure of the teneurin-latrophilin complex: Alternative splicing controls synapse specificity by a novel mechanism

“…1C) (Feng et al, 2002;Oohashi et al, 1999;Vysokov et al, 2016). Tenm's have central roles in tissue polarity, embryogenesis, heart development, axon guidance, and synapse formation (Berns et al, 2018;Boucard et al, 2014;Doyle et al, 2006;Hong et al, 2012;Levine et al, 1994;Mosca and Luo, 2014;Silva et al, 2011;Woelfle et al, 2016); and are linked to various diseases including neurological disorders, developmental problems, various cancers and congenital general anosmia (Aldahmesh et al, 2012;Alkelai et al, 2016;Chassaing et al, 2016;Graumann et al, 2017;Hor et al, 2015;Talamillo et al, 2017;Ziegler et al, 2012). Lphn's (Lphn1-3 in mammals) belong to the adhesion-type Gprotein coupled receptor (GPCR) family (Krasnoperov et al, 1996;Lelianova et al, 1997) (Sugita et al, 1999) and have a large N-terminal ECR (>800 amino acids) in addition to their signaling seven-pass transmembrane domain and cytoplasmic tail ( Fig.…”