Abstract
Although squamous cell carcinomas (SqCCs) of the lungs, head and neck, oesophagus, and cervix account for up to 30% of cancer deaths, the mechanisms that regulate disease progression remain incompletely understood. Here, we use gene transduction and human tumor xenograft assays to establish that the tumour suppressor Cell adhesion molecule 1 (CADM1) inhibits SqCC proliferation and invasion, processes fundamental to disease progression. We determine that the extracellular domain of CADM1 mediates these effects by forming a complex with HER2 and integrin α6β4 at the cell surface that disrupts downstream STAT3 activity. We subsequently show that treating CADM1 null tumours with the JAK/STAT inhibitor ruxolitinib mimics CADM1 gene restoration in preventing SqCC growth and metastases. Overall, this study identifies a novel mechanism by which CADM1 prevents SqCC progression and suggests that screening tumours for loss of CADM1 expression will help identify those patients most likely to benefit from JAK/STAT targeted chemotherapies.
Highlights
Invasive, metastatic squamous cell carcinomas (SqCCs) of the lungs, head and neck, oesophagus, and cervix are responsible for over 400,000 deaths per year[1]
These results suggest that screening SqCC tumours for loss of Cell adhesion molecule 1 (CADM1) expression will help identify patients at greatest risk of disease progression and most likely to benefit from JAK/STAT targeted chemotherapies
We demonstrate that CADM1 inhibits SqCC progression via a mechanism involving HER2 and ITGα 6β 4-mediated STAT3 inhibition (Fig. 7).Our results indicate that the extracellular domain of CADM1 is responsible for suppressing tumour progression, consistent with previous studies of human colorectal cancer cells[14,15]
Summary
Metastatic squamous cell carcinomas (SqCCs) of the lungs, head and neck, oesophagus, and cervix are responsible for over 400,000 deaths per year[1]. SqCC progression involves acquisition of epithelial-to-mesenchymal transition (EMT) phenotypes including enhanced tumour cell motility, increased cell proliferation, elevated cell invasiveness, and reduced cell adhesiveness, all of which contribute to uncontrolled tumour growth and multi-organ metastases[2] These changes are accompanied by increased MMP production, reduced E-cadherin protein abundance, and elevated Twist[1] and Snail expression[3,4,5]. We demonstrate that the extracellular domain of CADM1 restricts tumour growth and metastases by interacting with HER2 and integrin α 6β 4 at the cell surface We establish that this CADM1-HER2-Itgα 6β 4 signaling complex reduces downstream STAT3 activity, an important regulator of SqCC proliferation and invasion. These results suggest that screening SqCC tumours for loss of CADM1 expression will help identify patients at greatest risk of disease progression and most likely to benefit from JAK/STAT targeted chemotherapies
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