Jian Lu, Marko Kornmann, Benno Traub
The precise mechanistic role of Interleukin-13 receptor alpha-2 (IL-13Rα2) in colorectal cancer (CRC) remains elusive, specifically regarding whether it functions as an active signaling receptor or a passive decoy. Its unique role in metastatic phenotypic plasticity remains poorly understood. We identified IL-13Rα2 as a powerful oncogenic signaling hub that significantly increases CRC cell proliferation, migration, and colony formation using shRNA knockdown and CRISPR activation to modify IL-13Rα2 across a range of CRC cell lines with different baseline characteristics. Most importantly, we found that its regulation of the epithelial-mesenchymal transition (EMT) is highly context-dependent. IL-13Rα2 controls the mesenchymal phenotype in highly plastic cells in a partial-EMT (p-EMT) stage (such as SW-480 and SW-620). Its removal completely reverses EMT and collapses core plasticity-driving nodes, such as AGR2 and p63. On the other hand, IL-13Rα2 precisely functions as a phenotypic amplifier limited by the cellular epigenetic landscape in strictly epithelial cells (such as HT-29), where it controls cellular survival but does not initiate EMT. The STAT6 signaling cascade is monopolized by IL-13Rα2. Targeted downregulation eliminates IL-13-induced STAT6 phosphorylation, which in turn causes severe cell cycle dysregulation marked by a delayed G1/S transition and intra-S phase arrest. In conclusion, our research demonstrates that IL-13Rα2 is a crucial, context-dependent signaling receptor that maintains the p-EMT state and malignant progression via the STAT6 axis, making it a precise therapeutic target for advanced, phenotypically plastic colorectal cancer.