Brain metastases: It takes two factors for a primary cancer to metastasize to brain

Abstract

Brain metastasis of a cancer is a malignant disease with high mortality, but the cause and the molecular mechanism remain largely unknown. Using the samples of primary tumors of 22 cancer types in the TCGA database, we have performed a computational study of their transcriptomic data to investigate the drivers of brain metastases at the basic physics and chemistry level. Our main discoveries are: (i) the physical characteristics, namely electric charge, molecular weight, and the hydrophobicity of the extracellular structures of the expressed transmembrane proteins largely affect a primary cancer cell's ability to cross the blood-brain barrier; and (ii) brain metastasis may require specific functions provided by the activated enzymes in the metastasizing primary cancer cells for survival in the brain micro-environment. Both predictions are supported by published experimental studies. Based on these findings, we have built a classifier to predict if a given primary cancer may have brain metastasis, achieving the accuracy level at AUC = 0.92 on large test sets.

Keywords: blood-brain barrier; brain metastasis; brain microenvironment; metabolic reprogramming; seed-soil hypothesis.

Figure 1

Key statistics. (A) The ROC curve of our trained classifier using four physical features. (B) Predicted FR levels in BMPs and NBMPs. (C) The ROC curve of our second classifier based on the expressions of the 20 selected enzymes. (D) The ROC curve of the integrated classifier using the combined features.

Figure 2

TPM-based expression levels of the 20 selected enzyme genes. Enzymes that catalyze H⁺-producing reactions are marked in red. (A) ARSA. (B) CANT1. (C) CASK. (D) CERK. (E) EPHA4. (F) EPHX2. (G) EYA4. (H) EZH2. (I) FMO6P. (J) FYN. (K) GCAT. (L) GLYATL2. (M) MYO3A. (N) NMNAT2. (O) PDE11A. (P) PDE3A. (Q) PGLS. (R) ULK1. (S) XDH. (T) YARS1.