Abstract
Simple SummaryColorectal cancer (CRC) is a common and deadly form of cancer. Non-erythroid spectrin αII (SPTAN1), a protein of the cytoskeleton, is thought to be involved in CRC development and progression. In this study, we explore whether measuring SPTAN1 levels in resected CRC specimens might help to predict patient survival outcomes and response to chemotherapy. Indeed, we find that higher SPTAN1 protein and mRNA levels in CRC specimens associate with longer patient survival times. Using cell culture experiments, we then show that cells with lower SPTAN1 levels are less susceptible to FOLFOX chemotherapy, a standard treatment regimen for patients with CRC. Overall, our study underscores the importance of cytoskeletal proteins in shaping tumour biology and treatment responses and nominates SPTAN1 as a biomarker to improve patient stratification and refine therapeutic decisions in CRC.Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality. In a cohort of 189 patients with CRC, we recently showed that expression of the cytoskeletal scaffolding protein non-erythroid spectrin αII (SPTAN1) was lower in advanced metastatic tumours. The aim of the present study was to clarify the association of intratumoural SPTAN1 expression levels with treatment and survival outcomes in patients with CRC. The analysis was based on histologic assessment of SPTAN1 protein levels in our own CRC cohort, and transcriptome data of 573 CRC cases from The Cancer Genome Atlas (TCGA). We first establish that high intratumoural levels of SPTAN1 protein and mRNA associate with favourable survival outcomes in patients with CRC. Next, a response prediction signature applied to the TCGA data reveals a possible link between high SPTAN1 transcript levels and improved patient responses to FOLFOX chemotherapy. Complementary in vitro experiments confirm that SPTAN1 knockdown strains of the colon cancer cell lines HT-29, HCT116 mlh1-2 and Caco-2 are less responsive to FOLFOX chemotherapy compared with SPTAN1-proficient control strains. Taken together, we identify SPTAN1 as a novel prognostic biomarker in CRC and show that SPTAN1 expression levels may predict patient responses to chemotherapy. These investigations illustrate how an affordable, histology-based diagnostic test could directly impact therapeutic decision-making at the bedside.
Highlights
Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality in both men and women [1]
We find that upregulation of actin cytoskeletal genes in bulk expression data is associated with increasing tumour stage and poor survival outcomes, whereas increased expression of SPTAN1 and other genes involved in focal adhesion predicts better overall survival
Given that the predicted effects of SPTAN1 expression levels on tumour biology did not fully explain why SPTAN1-high colorectal tumours have better survival outcomes, we considered whether the observed survival advantage may result from a favourable response to FOLFOX chemotherapy in the SPTAN1-high group
Summary
Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality in both men and women [1]. The majority of colorectal tumours are sporadic in nature and arise from a well-defined sequence of somatic mutations termed the adenoma-carcinoma sequence [2]. Some fifteen per cent of colorectal tumours result from defective. DNA mismatch repair (MMR), which leads to the hypermutable phenotype known as microsatellite instability (MSI) [3]. MSI-high colorectal tumours develop either through germline mutations in one of the MMR genes or by epigenetic silencing of the MutL homolog 1 (MLH1) gene [3]. MSI-high CRCs have a better prognosis and are less likely to metastasise than microsatellite stable CRCs [4,5]. The molecular explanation for their reduced metastatic potential remains unknown
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
