Abstract
Mesenchymal stem cells (MSCs) are recruited and activated by solid tumors and play a role in tumor progression and metastasis. Here we show that MSCs promote metastasis in a panel of non-small cell lung cancer (NSCLC) cells. MSCs elicit transcriptional alterations in lung cancer cells leading to increased expression of factors implicated in the epithelial-to-mesenchymal transition (EMT) and secreted proteins including matrix metalloproteinase-9 (MMP9). MSCs enhance secretion of enzymatically active MMP9 in a panel of lung adenocarcinoma cells. High expression of MMP9 is linked to low survival rates in lung adenocarcinoma patients. Notably, we found that ABL tyrosine kinases are activated in MSC-primed lung cancer cells and functional ABL kinases are required for MSC-induced MMP9 expression, secretion and proteolytic activity. Importantly, ABL kinases are required for MSC-induced NSCLC metastasis. These data reveal an actionable target for inhibiting MSC-induced metastatic activity of lung adenocarcinoma cells through disruption of an ABL kinase-MMP9 signaling axis activated in MSC-primed lung cancer cells.
Highlights
Lung cancer is the leading cause of cancer mortality worldwide with an overall five-year survival rate of less than 20% [1, 2]
In order to investigate the effect of Mesenchymal stem cells (MSCs) on lung tumor progression and metastasis, we employed epidermal growth factor receptor (EGFR)-mutant human PC9 and HCC827 non-small cell lung cancer (NSCLC) cells that were primed by pre-incubation with or without bone marrow-derived MSCs for 3 days
FACS analysis showed that MSCs comprise approximately 5–6% of the total number of cells co-cultured with Tomato+ lung cancer cells (S1A Fig)
Summary
Lung cancer is the leading cause of cancer mortality worldwide with an overall five-year survival rate of less than 20% [1, 2]. ~40% of lung cancer patients have metastasis at the time of diagnosis which is associated with increased morbidity and mortality [3]. Patients with non-small cell lung cancer (NSCLC) harboring mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase are at high risk of developing metastasis following the emergence of therapy-resistance to EGFR targeted therapies [4, 5]. While much progress has been made on the identification of tumor-intrinsic oncogenic drivers and pathways implicated in lung tumor progression and metastasis, much less is known regarding the role of stromal cells in the regulation of lung cancer metastasis. Mesenchymal stem cells (MSCs) are heterogenous stromal cells present in most tissues that play important roles in tissue regeneration, wound healing, as well as tumor progression and metastasis [6, 7]. MSCs have been shown to migrate to tumors, undergo activation, and engage
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