Loss of STIM2, but not of STIM1, drives colorectal cancer metastasis through metabolic reprogramming and the ATF4 ER stress pathway

The large amounts of calcium (Ca²⁺) stored in the endoplasmic reticulum (ER) and the controlled release of this Ca²⁺ store into the cytosol regulate many cellular functions, and altered ER Ca²⁺ homeostasis induces ER stress. Stromal-interacting molecules 1 and 2 (STIM1/2) are homologous ER-resident Ca²⁺ sensors that synergistically activate cytosolic Ca²⁺ influx through Orai channels to promote Ca²⁺-dependent changes in gene expression and ER Ca²⁺ refilling. Here, we demonstrated that reduced abundance of STIM2, but not that of STIM1, was associated with poor prognosis in colorectal cancer (CRC). STIM2-deficient CRC cells showed enhanced ER Ca²⁺ content in a manner dependent on the ER Ca²⁺ pump SERCA2, increased expression of genes associated with protein translation, and transcriptional and metabolic rewiring. STIM2 deficiency in CRC xenografts led to increased tumor size, invasion, and metastasis. STIM2 loss activated the expression of genes involved in ER stress responses in a manner dependent on the chaperone BiP and the transcription factor ATF4 and independent of Orai channels. These results suggest that loss of STIM2 may inform CRC prognosis.