Cancer-associated splicing alterations represent a key epigenetic mechanism underlying tumor biological changes that drive disease progression. DCLK1-S, a splice variant of the stem cell marker DCLK1, has been shown to promote tumorigenesis in gastrointestinal malignancies. However, the differences in their activities are not well characterized. Here, Ge, Fan, and colleagues characterize the molecular functions of DCLK1-S in esophageal squamous cell carcinoma (ESCC). Ablation of DCLK1-S was shown to inhibit ESCC cell proliferation, migration, and invasion in vitro, and overexpression of the shortened isoform was associated with markers of epithelial–mesenchymal transition. These effects were mediated through the MAPK pathway, leading to upregulation of MMP2 and stemness regulators such as Snail and Slug. Critically, these effects were reversible with ERK inhibitors, suggesting a potential therapeutic option for ESCC tumors that are reliant on this splicing event.