HER2 drives lung fibrosis by activating a metastatic cancer signature in invasive lung fibroblasts.
Xue LiuYan GengJiurong LiangAna Lucia CoelhoChangfu YaoNan DengYizhou WangKristy DaiGuanling HuangTing XieNingshan LiuSimon Coyle RowanForough TaghavifarVrishika KulurZhenqiu LiuBarry R StrippCory M HogaboamDianhua JiangPaul W NoblePublished in: The Journal of experimental medicine (2022)
Progressive tissue fibrosis, including idiopathic pulmonary fibrosis (IPF), is characterized by excessive recruitment of fibroblasts to sites of tissue injury and unremitting extracellular matrix deposition associated with severe morbidity and mortality. However, the molecular mechanisms that control progressive IPF have yet to be fully determined. Previous studies suggested that invasive fibroblasts drive disease progression in IPF. Here, we report profiling of invasive and noninvasive fibroblasts from IPF patients and healthy donors. Pathway analysis revealed that the activated signatures of the invasive fibroblasts, the top of which was ERBB2 (HER2), showed great similarities to those of metastatic lung adenocarcinoma cancer cells. Activation of HER2 in normal lung fibroblasts led to a more invasive genetic program and worsened fibroblast invasion and lung fibrosis, while antagonizing HER2 signaling blunted fibroblast invasion and ameliorated lung fibrosis. These findings suggest that HER2 signaling may be a key driver of fibroblast invasion and serve as an attractive target for therapeutic intervention in IPF.
Keyphrases
- idiopathic pulmonary fibrosis
- extracellular matrix
- interstitial lung disease
- small cell lung cancer
- squamous cell carcinoma
- cell migration
- end stage renal disease
- randomized controlled trial
- chronic kidney disease
- ejection fraction
- newly diagnosed
- gene expression
- early onset
- young adults
- papillary thyroid
- prognostic factors
- signaling pathway
- peritoneal dialysis
- dna methylation
- wound healing
- weight gain
- body mass index
- quality improvement
- drug induced
- physical activity
- lymph node metastasis