The Spatial Distribution of Brain Metastasis Is Determined by the Heterogeneity of the Brain Microenvironment

It is now understood that brain metastases do not occur randomly but have distinct spatial patterns depending on the origin of the cancer. According to the “seed and soil” hypothesis, the final colonization of metastatic cells is the result of their adaptation to the altered environment. To investigate the most favorable microenvironment for brain metastasis, we analyzed neuroimaging data from 177 patients with breast cancer brain metastasis and 548 patients with lung cancer brain metastasis to create a replicable probabilistic map of metastatic locations. Additionally, we used population-based data from open repositories to generate brain atlases of diverse microenvironment features, including gene expression, functional connectivity, glucose metabolism, and neurotransmitter transporters/receptors. We then compared the spatial correlation between brain metastasis frequency and these features, after which we constructed a general linear model to identify the most significant variables that contributed to tumor location predilection. Our findings revealed that brain metastases from breast cancer and lung cancer had distinct radiographic characteristics and distribution patterns. Breast cancer tended to metastasize in brain regions with decreased expression of genes associated with immunity and metabolism and reduced levels of connectomic hubness and glucose metabolism. In contrast, lung cancer had a higher probability of metastasizing in regions with active metabolism. Moreover, neurotransmitter systems play various roles in determining tumor location. These results provide new insights into the adaptation of metastatic cells to the brain microenvironment and illustrate how factors on diverse biological scales can affect the colonization of brain metastases.