Bidirection activation of stem-like programs in metastatic cancer and alveolar type II cells within the niche [RNA-seq]

A key step for metastatic outgrowth involves the generation of a deeply altered microenvironment (niche) that supports the malignant behavior of cancer cells. However, it is unclear whether a fundamental program driving the generation of this de novo cellular environment can be identified. Here, by focusing on breast cancer metastasis to the lung, we describe a cancer-dependent chromatin remodeling and activation of developmental programs in alveolar type II (AT2) cells. We have identified a relationship linking high metastatic competency in the lung with the induction of a multilineage state in AT2 cells in the niche. In turn, this cancer-induced reprogramming of AT2 cells promoted stem-like features in the cancer cells. In conclusion, we propose the concept of “reflected stemness” during metastatic niche initiation, whereby metastatic cells reprogram the local tissue into a stem-like state that enhance intrinsic cancer-initiating potential, creating a positive feedback loop where tumorigenic programs may be amplified. Overall design: To investigate the transcriptional changes that occurs in cancer cells during outgrowth in the lung, we compared the RNA of 4T1 cancer cells growing in the dish (in vitro) and 4T1 cancer cells isolated from the lungs of BALB/c mice (in vivo) 7 days after tail vein injection. For isolation of lung epithelial cells, we injected 0.8x10^6 labeling-4T1 cancer cells and collected the lungs 7 days after tail vein injection for FACS sorting. For each biological replicate, we pooled a total of 5 lungs to obtain enough niche lung epithelial cells.