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. Highlights STIM2 regulates ER Ca 2+ homeostasis independently of Orai and SOCE. STIM2 downregulation in colorectal cancer cells causes enhanced ER Ca 2+ and is associated with poor patient prognosis. STIM2 downregulation induces PERK/ATF4 dependent ER stress in colorectal cancer. Increased ER stress drives colorectal cancer metabolic reprogramming, growth, and metastasis.