Abstract P107: Gelsolin Promotes Resistance to 5-Fluorouracil in Colorectal Cancer through TFEB-dependent autophagy

Abstract

Despite advances in colorectal cancer management using a 5-Fluorouracil (5-FU)-based regime, recurrence after chemotherapy is the barrier to effective clinical outcomes for these patients. Accumulating evidence suggests regulators of actin cytoskeleton play critical roles in resistance to drug treatment and disease progression. Here, we identify gelsolin, an actin depolymerizing factor, as a novel autophagy regulator linking to 5-FU resistance in colorectal cancer. By analysing meta-cohorts of colorectal cancer clinical data, we find that elevated gelsolin expression levels in tumour tissues correlate with shorter overall and relapse-free patient survival. Following 5-FU treatment, gelsolin protects colorectal cancer cells from 5-FU-induced cell death through activating autophagy as a pro-survival pathway. Using both in vitro and in silico approaches, we show that gelsolin regulates autophagy via transcription factor EB (TFEB)-mediated lysosome activation. Actin regulation function is required for gelsolin-mediated TFEB translocation, where loss-of-function mutant gelsolin fails to activate TFEB and autophagy in response to 5-FU. Our findings translate to patients’ outcomes in that colorectal cancer patients, especially those with advance stage disease and treated with chemotherapy, with concurrent high gelsolin and high cathepsin expression show poorer overall and relapse-free survival. Our study unveils a novel role of gelsolin in regulating cell autophagy towards drug resistance and paves the way for gelsolin targeting drug development to improve the poor outcomes of current 5-FU-based therapies.