Loss of STIM2 in colorectal cancer drives growth and metastasis through metabolic reprogramming and PERK-ATF4 endoplasmic reticulum stress pathway

The endoplasmic reticulum (ER) stores large amounts of calcium (Ca(2+)), and the controlled release of ER Ca(2+) regulates a myriad of cellular functions. Although altered ER Ca(2+) homeostasis is known to induce ER stress, the mechanisms by which ER Ca(2+) imbalance activate ER stress pathways are poorly understood. Stromal-interacting molecules STIM1 and STIM2 are two structurally homologous ER-resident Ca(2+) sensors that synergistically regulate Ca(2+) influx into the cytosol through Orai Ca(2+) channels for subsequent signaling to transcription and ER Ca(2+) refilling. Here, we demonstrate that reduced STIM2, but not STIM1, in colorectal cancer (CRC) is associated with poor patient prognosis. Loss of STIM2 causes SERCA2-dependent increase in ER Ca(2+), increased protein translation and transcriptional and metabolic rewiring supporting increased tumor size, invasion, and metastasis. Mechanistically, STIM2 loss activates cMyc and the PERK/ATF4 branch of ER stress in an Orai-independent manner. Therefore, STIM2 and PERK/ATF4 could be exploited for prognosis or in targeted therapies to inhibit CRC tumor growth and metastasis.