The site of breast cancer metastases dictates their clonal composition and reversible transcriptomic profile
Metastatic tumors originating from notoriously aggressive triple-negative breast cancer that emerge in the lungs contain a more diverse array of cancer cells than those that arise in the liver, according to a new study in mice and organs from deceased cancer patients. The study also identified a set of genes that distinguish lung and liver metastases; together, the findings may inform future research on how targeted therapies impact tumors across various microenvironments. While scientists have known that the presence of distinct tumor cell populations within the same tumor drives breast cancer progression, it has not been fully understood why this dangerous cellular diversity develops within some tumors and not others. To investigate how metastases vary based on host tissue type, Jean Berthelet and colleagues optimized a new optical barcoding strategy and analyzed 31 triple-negative breast cancer subclones (subpopulations of cells descended from cancer cells). The researchers injected fluorescently labeled cells into the mammary fat pads of mice with cancer and mapped the clonal composition of thousands of metastases in the lungs and liver, where triple-negative breast cancer cells tend to spread. They found that the inflammatory tumor necrosis factor alpha (TNF-? ) pathway was particularly upregulated in metastases in the lungs compared with those in the liver, with some genes in this pathway potentially responsible for the success of lung metastases. Berthelet et al. also collected 4 lung and 7 liver metastases from autopsies of 3 patients with breast cancer, confirming that the genes they identified were also expressed differently between the lungs and liver in humans.