Altered Expression and Splicing of ESRP1 in Malignant Melanoma Correlates with Epithelial–Mesenchymal Status and Tumor-Associated Immune Cytolytic Activity

Abstract

Melanoma is one of the major cancer types for which new immune-based cancer treatments have achieved promising results. However, anti-PD-1 and anti-CTLA-4 therapies are effective only in some patients. Hence, predictive molecular markers for the development of clinical strategies targeting immune checkpoints are needed. Using The Cancer Genome Atlas (TCGA) RNAseq data, we found that expression of ESRP1, encoding a master splicing regulator in the epithelial-mesenchymal transition (EMT), was inversely correlated with tumor-associated immune cytolytic activity. That association holds up across multiple TCGA tumor types, suggesting a link between tumor EMT status and infiltrating lymphocyte activity. In melanoma, ESRP1 mainly exists in a melanocyte-specific truncated form transcribed from exon 13. This was validated by analyzing CCLE cell line data, public CAGE data, and RT-PCR in primary cultured melanoma cell lines. Based on ESRP1 expression, we divided TCGA melanoma cases into ESRP1-low, -truncated, and -full-length groups. ESRP1-truncated tumors comprise approximately two thirds of melanoma samples and reside in an apparent transitional state between epithelial and mesenchymal phenotypes. ESRP1 fulllength tumors express epithelial markers and constitute about 5% of melanoma samples. In contrast, ESRP1-low tumors express mesenchymal markers and are high in immune cytolytic activity as well as PD-L2 and CTLA-4 expression. Those tumors are associated with better patient survival. Results from our study suggest a path toward the use of ESRP1 and other EMT markers as informative biomarkers for immunotherapy.

Epithelial splicing regulatory protein 1 and 2 paralogues correlate with splice signatures and favorable outcome in human colorectal cancer

“…This is in agreement to pancreatic ductal adenocarcinoma where increased ESRP1 expression was related to better survival [18], but in contrast to breast cancer patients where ESRP1 was associated with lower survival rate [16]. Recent findings in melanoma patients identified a link between low ESRP1 expression in tumor tissue and tumor-associated immune cytolytic activity with better patient survival [29]. Whether ESRPs play a positive and/or negative role during cancer progression in specific tumors must be elucidated on a tumor-by-tumor basis and considering homogeneity of tumor tissue.…”

Snail Driving Alternative Splicing of CD44 by ESRP1 Enhances Invasion and Migration in Epithelial Ovarian Cancer

“…It has been reported that ESRP1 is critical in regulating cancer subtype specific alternative splicing programs and in mediating EMT specific splicing programs [35,36]. This study characterized the mechanisms and effects of ESRP1 on metastatic behavior in EOC.…”

Epigenomic annotation of noncoding mutations identifies mutated pathways in primary liver cancer

“…Knockdown of ESRP1 activity in breast cancer cells restored the non-EMT-inducing isoform of CD44 and suppressed metastasis [50], evidence that ESRP1 acts as an oncogene. ESRP1 acts as a master regulator of EMT in melanoma [51] and somatotroph adenomas [52]. However, upregulation of ESRP1 is correlated with fewer metastasis and better prognosis in pancreatic ductal adenocarcinoma [53], and acts a tumor suppressor in colorectal cancer [54], reflecting the cell type-specific nature of cancer genes [44].…”