FOXM1 expression is induced by the brain microenvironment and supports CRC brain metastatic adaptation

Colorectal cancer (CRC) is a leading cause of cancer-related mortality in the Western world. While brain metastasis (BMs) are relatively uncommon in CRC, they represent the fourth most frequent cause of BMs overall, and their occurrence is increasingly recognized as a complication in advanced CRC, associated with poor prognosis and limited treatment options. The brain microenvironment presents unique metabolic challenges, including low oxygen levels and restricted lipid availability. In order to survive in this hostile environment, CRC cells must acquire metabolic adaptations allowing them to survive and proliferate. To identify key drivers that enable CRC cells to metastasize to and survive within the brain, we conducted a transcriptomic screen of CRC BMs and compared it to liver metastasis (LMs). FOXM1, a transcription factor critical for tumor progression, was identified among the upregulated genes, and these results were validated by immunohistochemistry. To study the role of the brain microenvironment in mediating FOXM1 expression, we examined FOXM1 expression in CRC cell lines grown in either astrocyte-conditioned media (A-CM) or hepatocyte-conditioned media (H-CM). We observed a marked upregulation of FOXM1 following exposure to A-CM. Moreover, using an intracranial CRC BMs mouse model, a significant FOXM1 overexpression was observed. In accordance with the importance of fatty acid metabolism in BMs, our study revealed a significant correlation between FOXM1 and fatty acid synthase (FASN) in the CRC BMs, in agreement with public databases. These findings suggest that FOXM1 plays a key role in CRC BMs progression and may serve as a promising therapeutic target in this challenging disease setting.