Bidirection activation of stem-like programs in metastatic cancer and alveolar type II cells within the niche [ATAC-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 chromatin remodeling that happens in AT2 cells from two different metastatic tumor models. Syngeneic BALB/c mice (6- to 8-week-old) were intravenously injected with 0.8 x 106 labeling-4T1 or labeling-CT26 tumor cells and lungs were collected 7 days after tail vein injection. Three biological independent samples were generated for each condition (4T1; AT2 distal and AT2 niche / CT26; AT2 distal and AT2 niche) and each sample was prepared by pooling 5 lungs.