Hypoxia drives the formation of lung micropapillary adenocarcinoma through hypoxia-inducible factor-1a (RNA-seq). Hypoxia drives the formation of lung micropapillary adenocarcinoma through hypoxia-inducible factor-1a (RNA-seq)

Micropapillary adenocarcinoma (MPC) is an aggressive histologic subtype of lung adenocarcinoma (LUAD). MPC is composed of small clusters of cancer cells exhibiting inverted polarity. However, the mechanism underlying its formation is poorly understood. Here we show that hypoxia is involved in MPC formation. Spatial transcriptome analysis with human LUAD tissue suggested that hypoxia-inducible factor (HIF)-1 signaling is activated in MPC. Hypoxia induced the formation of MPC-like structures (MLSs) with inverted polarity in a three-dimensional culture system using A549 human LUAD cells, and HIF-1α was indispensable for MLS formation. RNA sequencing analysis demonstrated that A549 cells forming MLSs exhibited a gene expression signature similar to that of lung MPC. Moreover, MLS formation enhanced the resistance of A549 cells to natural killer cell cytotoxicity. Our findings suggest that hypoxia drives lung MPC formation through HIF-1α and that immune escape from natural killer cells might underlie the aggressiveness of MPC. Overall design: To characterize the hypoxia-induced MLSs in detail, we performed RNA-seq analysis in A549 cells cultured in the usual 2D culture system or the 3D culture system under normoxia or hypoxia.