FOXM1 drives metabolic adaptations in colorectal cancer brain metastases and represents a potential therapeutic target

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. Among the upregulated genes, FOXM1 was identified, a transcription factor critical for tumor progression. This was further validated by immunohistochemistry in human samples. To study the role of brain microenvironment in mediating FOXM1 upregulation, CRC cells were cultured in either astrocyte-conditioned media (A-CM) or compared to hepatocyte-conditioned media (H-CM). CRC cells exposed to A-CM exhibited markedly higher FOXM1 expression. Moreover, using an in vivo model of intracranial CRC BM mouse model demonstrated significant FOXM1 overexpression in CRC cells following brain injection. And notably, our study revealed a significant correlation between FOXM1 and fatty acid synthase (FASN) in the brain microenvironment. These findings suggest that FOXM1 plays a key role in CRC brain metastasis and may serve as a promising therapeutic target. Targeting FOXM1 could provide novel treatment strategies for CRC patients with BMs, potentially improving outcomes in this challenging disease setting.