Expression ratio of the TGF\u03b2-inducible gene MYO10 is prognostic for overall survival of squamous cell lung cancer patients and predicts chemotherapy response

D Dvornikov,H Busch,M Boerries,F J Herth,T Muley,J Timmer,M Szczygieł,A Warth,S Ohse,I Titkova,H Dienemann,U Klingmüller,M Rosenblatt,M Thomas,M Schilling,M A Schneider,M Meister

doi:10.1038/s41598-018-27912-1

Abstract

In lung cancer a deregulation of Transforming Growth Factor-β (TGFβ) signaling has been observed. Yet, the impact of TGFβ in squamous cell carcinoma of the lung (LUSC) remained to be determined. We combined phenotypic and transcriptome-wide studies and showed that the stimulation of the LUSC cell line SK-MES1 with TGFβ results in an increase of migratory invasive properties. The analysis of the dynamics of gene expression by next-generation sequencing revealed that TGFβ stimulation orchestrates the upregulation of numerous motility- and actin cytoskeleton-related genes. Among these the non-muscle myosin 10 (MYO10) showed the highest upregulation in a LUSC patient cohort of the Cancer Genome Atlas (TCGA). Knockdown of MYO10 abrogated TGFβ-induced collagen gel invasion of SK-MES1 cells. The analysis of MYO10 mRNA expression in paired tissues of 151 LUSC patients with corresponding 80-month clinical follow-up data showed that the mRNA expression ratio of MYO10 in tumor and tumor-free tissue is prognostic for overall survival of LUSC patients and predictive for the response of these patients to adjuvant chemotherapy. Thus, MYO10 represents a new clinical biomarker for this aggressive disease and due to its role in cellular motility and invasion could serve as a potential molecular target for therapeutic interventions in patients with LUSC.

Highlights

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortalities
SK-MES1 cells usually grow in tight epithelial colonies, but after treatment with Transforming Growth Factor-β (TGFβ) they lost cell-cell contacts and acquired an elongated spindle-shaped morphology (Fig. 1B), a feature commonly observed upon TGFβ-induced epithelial-to-mesenchymal transition (EMT)
We investigated TGFβ-induced changes in signal transduction, gene expression and phenotypic responses in the LUSC cell line SK-MES1 to shed light on TGFβ-induced mechanisms that might contribute to tumor progression in LUSC

Summary

Introduction

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortalities. There is an urgent need to gain insights into mechanism contributing to LUSC in order to establish mechanism-based biomarkers that help clinicians to identify patients at the highest risk for disease progression and therapy resistance. Both early metastasis and therapy resistance are attributed to cancer cells undergoing epithelial-to-mesenchymal transition (EMT) and acquiring a more invasive phenotype with cancer stem cell-like properties[5]. We combined phenotypic and transcriptome-wide approaches to determine TGFβ-induced dynamic changes in the transcriptome of a LUSC cell line and thereby derived a candidate prognostic biomarker that we validated in a clinical cohort

Methods

Results

Conclusion