Gene expression adaptation of metastases to their host tissue.

Adaptation of metastatic cells to their host tissue determines the pathogenicity of cancer. Yet, it remains elusive to what extent the host environment drives gene expression programs in metastatic cells. We present a new concept to identify adaptive mechanisms that enable metastases to establish themselves in a novel tissue context. We generated quadruple-paired single-cell RNA-sequencing data from malignant and benign tissues from untreated donors with colorectal adenocarcinoma and liver metastasis. Utilizing a computational approach, we deduce tissue-adaptive expression patterns by identifying genes that consistently adapt to the host tissue. Expression changes in metastases are reminiscent of benign liver epithelial cells, including basic cellular functions such as energy metabolism, as well as tissue-specific pathways such as the regulation of lipid metabolism by peroxisome proliferator-activated receptor alpha (PPAR-α). This approach identifies the molecular adaptation of cancers to the host environment, which potentially increases the pathogenicity of metastatic cells, proposing a new therapeutic strategy to target adaptive processes.