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

A key step for metastatic outgrowth involves the generation of a deeply altered microenvironment (niche) that supports the malignant behavior of cancer cells. The complexity of the metastatic niche has posed a significant challenge in elucidating the underlying programs driving its origin. Here, by focusing on early stages of breast cancer metastasis to the lung in mice, we describe a cancer-dependent chromatin remodeling and activation of developmental programs in alveolar type 2 (AT2) cells within the niche. We show that metastatic cells can prime AT2 cells into a reprogrammed multilineage state. In turn, this cancer-induced reprogramming of AT2 cells promoted stem-like features in cancer cells and enhanced their initiation capacity. In conclusion, we propose the concept of "reflected stemness" as an early phenomenon during metastatic niche initiation, wherein metastatic cells reprogram the local tissue into a stem-like state that enhances intrinsic cancer-initiating potential, creating a positive feedback loop where tumorigenic programs are amplified. ATAC-seq data of AT2 cells in the distal lung or the metastatic niche of breast and colon cancer pulmunary metastasis. RNA-seq data of EpCAM+ cells isolated from the distal lung, the metastatic niche of 4T1 shControl and of 4T1 shSox9 cell's niche. RNA-seq 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.