title: CADM1 inhibits squamous cell carcinoma progression by reducing STAT3 activity.
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.
authors.affiliation: Lungs for Living Research Centre, University College London, UK.
authors.forename: Sabari
authors.initials: S
authors.lastname: Vallath
authors.affiliation: Lungs for Living Research Centre, University College London, UK.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Sage
authors.affiliation: Lungs for Living Research Centre, University College London, UK.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Kolluri
authors.affiliation: Lungs for Living Research Centre, University College London, UK.
authors.forename: Sofia N
authors.initials: SN
authors.lastname: Lourenco
authors.affiliation: Lungs for Living Research Centre, University College London, UK.
authors.forename: Vitor S
authors.initials: VS
authors.lastname: Teixeira
authors.affiliation: Lungs for Living Research Centre, University College London, UK.
authors.forename: Suneeta
authors.initials: S
authors.lastname: Chimalapati
authors.affiliation: Lungs for Living Research Centre, University College London, UK.
authors.forename: P Jeremy
authors.initials: PJ
authors.lastname: George
authors.affiliation: Lungs for Living Research Centre, University College London, UK.
authors.forename: Sam M
authors.initials: SM
authors.lastname: Janes
authors.affiliation: Lungs for Living Research Centre, University College London, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Giangreco
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D039161:Integrin alpha6beta4 / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009570:Nitriles; D011720:Pyrazoles / Q000737:chemistry; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D039161:Integrin alpha6beta4; D008565:Membrane Proteins; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; C403514:CADM1 protein, human; C498598:Cadm1 protein, mouse; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C540383:ruxolitinib; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse