A pan-cancer study of class-3 semaphorins as therapeutic targets in cancer

Xiaoli Zhang,Jin Li,Brett Klamer,Lang Li,Soledad Fernandez

doi:10.1186/s12920-020-0682-5

Abstract

BackgroundInitially characterized as axon guidance factors, semaphorins also have been implicated to have critical roles in multiple physiological and developmental functions, including the regulation of immune responses, angiogenesis, organ formation, and the etiology of multiple forms of cancer. Moreover, their contribution in immunity and the regulation of tumour microenvironment is becoming increasingly recognized. Here, we provide a comprehensive analysis of class-3 semaphorins, the only secreted family of genes among veterbrate semaphorins, in terms of their expression profiles and their association with patient survival. We also relate their role with immune subtypes, tumour microenvironment, and drug sensitivity using a pan-cancer study.ResultsExpression profiles of class-3 semaphorins (SEMA3s) and their association with patient survival and tumour microenvironment were studied in 31 cancer types using the TCGA pan-cancer data. The expression of SEMA3 family varies in different cancer types with striking inter- and intra- cancer heterogeneity. In general, our results show that SEMA3A, SEMA3C, and SEMA3F are primarily upregulated in cancer cells, while the rest of SEMA3s are mainly down-regulated in the tested tumours. The expression of SEMA3 family members was frequently associated with patient overall survival. However, the direction of the association varied with regards to the particular SEMA3 isoform queried and the specific cancer type tested. More specifically, SEMA3A and SEMA3E primarily associate with a poor prognosis of survival, while SEMA3G typically associates with survival advantage. The rest of SEMA3s show either survival advantage or disadvantage dependent on cancer type. In addition, all SEMA3 genes show significant association with immune infiltrate subtypes, and they also correlate with level of stromal cell infiltration and tumour cell stemness with various degrees. Finally, our study revealed that SEMA3 genes, especially SEMA3C and SEMA3F may contribute to drug induced cancer cell resistance.ConclusionsOur systematic analysis of class-3 semaphorin gene expression and their association with immune infiltrates, tumour microenvironment and cancer patient outcomes highlights the need to study each SEMA3 member as a separate entity within each specific cancer type. Also our study validated the identification of class-3 semaphorin signals as promising therapeutic targets in cancer although further laboratory validation still needed.

Highlights

Characterized as axon guidance factors, semaphorins have been implicated to have critical roles in multiple physiological and developmental functions, including the regulation of immune responses, angiogenesis, organ formation, and the etiology of multiple forms of cancer
Class-3 semaphorins (SEMA3) gene expression in pan-cancer To understand the intrinsic expression pattern of SEMA3 genes, we examined the expression levels of the SEMA3 family members in all 31 cancer types available in The cancer genome atlas (TCGA) pan-cancer data (Summery of TCGA data are in Additional file 3: Table S1 and Additional file 4: Figure S1)
SEMA3A, SEMA3D, and SEMA3E showed relatively lower level of expression averaged across all cancer types compared to the rest of the SEMA3 family members, .i.e., SEMA3B, SEMA3C, SEMA3F and SEMA3G, where SEMA3F had the highest expression (Fig. 1a)

Summary

Introduction

Characterized as axon guidance factors, semaphorins have been implicated to have critical roles in multiple physiological and developmental functions, including the regulation of immune responses, angiogenesis, organ formation, and the etiology of multiple forms of cancer. We provide a comprehensive analysis of class-3 semaphorins, the only secreted family of genes among veterbrate semaphorins, in terms of their expression profiles and their association with patient survival We relate their role with immune subtypes, tumour microenvironment, and drug sensitivity using a pan-cancer study. Initially identified as axon guidance molecules, in recent years semaphorins have been recognized to have crucial roles in the regulation of diverse biological and pathophysiological processes, including angiogenesis, cancer tumourigenesis, inflammation, apoptosis, and immune response [3, 4] These multifaceted functions are attributed to activation of downstream signaling cascades mainly mediated by cell surface receptors plexins and neuropilins [5]. There has been so far no systemic study of this family of genes in different human cancers, and each of the genes was only studied in a few types of cancers and most of those studies were performed using cell lines and/or animal models

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