Epigenetic Rewiring of Metastatic Cancer to the Brain: Focus on Lung and Colon Cancers

SIMPLE SUMMARY: The epigenetic state within cells represents a layer for controlling homeostasis and cell differentiation. In cancer, this fine-tuned program is disrupted, resulting in cancer progression and, eventually, dissemination to distant organs. Here, we examine the epigenetic states of brain metastasis from colorectal and lung cancers and we compare those signatures with the ones detected in primary tumors. Our aim is to decipher which are the tumor type-specific regions whose deregulation is involved in metastatic dissemination to the brain and which signaling potentially confers an advantage to tumor cells to colonize the brain milieu. This information will shed light on the epi-mechanisms underpinning CRC and LuC cell dissemination to the brain and provide preliminary clues about the potential clinical value of epigenetics for brain metastasis diagnosis and therapeutic targeting. ABSTRACT: Distant metastasis occurs when cancer cells adapt to a tissue microenvironment that is different from the primary organ. This process requires genetic and epigenetic changes in cancer cells and the concomitant modification of the tumor stroma to facilitate invasion by metastatic cells. In this study, we analyzed differences in the epigenome of brain metastasis from the colon (n = 4) and lung (n = 14) cancer and we compared these signatures with those found in primary tumors. Results show that CRC tumors showed a high degree of genome-wide methylation compared to lung cancers. Further, brain metastasis from lung cancer deeply activates neural signatures able to modify the brain microenvironment favoring tumor cells adaptation. At the protein level, brain metastases from lung cancer show expression of the neural/glial marker Nestin. On the other hand, colon brain metastases show activation of metabolic signaling. These signatures are specific for metastatic tumors since primary cancers did not show such epigenetic derangements. In conclusion, our data shed light on the epi/molecular mechanisms that colon and lung cancers adopt to thrive in the brain environment.