Loss of STIM2, but not of STIM1, drives colorectal cancer metastasis through metabolic reprogramming and the ATF4 ER stress pathway
Menée à l'aide de données du projet "The Cancer Genome Atlas" et de xénogreffes de cancer colorectal sur des modèles murins, cette étude démontre que la perte d'expression de STIM2, et non de STIM1, favorise le développement de métastases via une augmentation du contenu du réticulum endoplasmique en Ca2+, une reprogrammation transcriptionnelle et une réorganisation métabolique impliquant le facteur de transcription ATF4 ainsi qu'un remodelage mitochondrial
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. The ER-resident Ca2+ sensor STIM2 may suppress colorectal cancer tumor progression and metastasis. When it metastasizes, colorectal cancer (CRC) has a poor prognosis. Pathak et al. found that loss of the ER Ca2+ sensor STIM2 in CRC correlated with poor prognosis in patients and enhanced both progression and metastasis of xenografts in mice. STIM2 loss was associated with increased ER Ca2+ content, transcriptional reprogramming and metabolic rewiring dependent on the ER stress transcription factor ATF4, and mitochondrial remodeling. These effects were specific to loss of STIM2, did not involve its role in store-operated Ca2+ entry, and were not replicated by loss of the structurally and functionally homologous STIM1. Thus, STIM2 loss may be a biomarker of more aggressive CRC. —Wei Wong
Science Signaling , résumé, 2025