Early stages of colorectal cancer (CRC) development are characterized by a complex rewiring of transcriptional networks resulting in changes in the expression of multiple genes. Here, we demonstrate that the deletion of a poorly studied tetraspanin protein Tspan6 in Apc^min/+ mice, a well-established model for premalignant CRC, resulted in increased incidence of adenoma formation and tumor size. We demonstrate that the effect of Tspan6 deletion results in the activation of EGF-dependent signaling pathways through increased production of the transmembrane form of TGF-α (tmTGF-α) associated with extracellular vesicles. This pathway is modulated by an adaptor protein syntenin-1, which physically links Tspan6 and tmTGF-α. In support of this, the expression of Tspan6 is frequently decreased or lost in CRC, and this correlates with poor survival. Furthermore, the analysis of samples from the epidermal growth factor receptor (EGFR)–targeting clinical trial (COIN trial) has shown that the expression of Tspan6 in CRC correlated with better patient responses to EGFR-targeted therapy involving Cetuximab. Importantly, Tspan6-positive patients with tumors in the proximal colon (right-sided) and those with KRAS mutations had a better response to Cetuximab than the patients that expressed low Tspan6 levels. These results identify Tspan6 as a regulator of CRC development and a potential predictive marker for EGFR-targeted therapies in CRC beyond RAS pathway mutations.

结直肠癌 (CRC) 发展的早期阶段的特征是转录网络的复杂重新布线，导致多个基因的表达发生变化。^{在这里，我们证明了在 Apc min/+}中删除了一个研究很少的四跨膜蛋白 Tspan6小鼠是一种成熟的癌前CRC模型，导致腺瘤形成和肿瘤大小的发生率增加。我们证明了 Tspan6 缺失的作用通过增加与细胞外囊泡相关的跨膜形式的 TGF-α (tmTGF-α) 的产生来激活 EGF 依赖性信号通路。该通路由衔接蛋白 syntenin-1 调节，该蛋白在物理上连接 Tspan6 和 tmTGF-α。为了支持这一点，CRC 中 Tspan6 的表达经常减少或丢失，这与较差的存活率相关。此外，对表皮生长因子受体 (EGFR) 靶向临床试验 (COIN 试验) 样本的分析表明，CRC 中 Tspan6 的表达与患者对西妥昔单抗靶向治疗的更好反应相关。重要的，近端结肠（右侧）肿瘤的 Tspan6 阳性患者和具有 KRAS 突变的患者对西妥昔单抗的反应比表达低 Tspan6 水平的患者更好。这些结果将 Tspan6 确定为 CRC 发展的调节因子，以及 RAS 通路突变之外的 CRC 中 EGFR 靶向治疗的潜在预测标志物。