title: RalA function in dermal fibroblasts is required for the progression of squamous cell carcinoma of the skin.
abstract: A large body of evidence has shown that stromal cells play a significant role in determining the fate of neighboring tumor cells through the secretion of various cytokines. How cytokine secretion by stromal cells is regulated in this context is poorly understood. In this study, we used a bioengineered human tissue model of skin squamous cell carcinoma progression to reveal that RalA function in dermal fibroblasts is required for tumor progression of neighboring neoplastic keratinocytes. This conclusion is based on the observations that suppression of RalA expression in dermal fibroblasts blocked tumorigenic keratinocytes from invading into the dermal compartment of engineered tissues and suppressed more advanced tumor progression after these tissues were transplanted onto the dorsum of mice. RalA executes this tumor-promoting function of dermal fibroblasts, at least in part, by mediating hepatocyte growth factor (HGF) secretion through its effector proteins, the Sec5 and Exo84 subunits of the exocyst complex. These findings reveal a new level of HGF regulation and highlight the RalA signaling cascade in dermal fibroblasts as a potential anticancer target.
authors.affiliation: Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Sowalsky
authors.forename: Addy
authors.initials: A
authors.lastname: Alt-Holland
authors.forename: Yulia
authors.initials: Y
authors.lastname: Shamis
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Garlick
authors.forename: Larry A
authors.initials: LA
authors.lastname: Feig
mesh_terms: D015820:Cadherins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005347:Fibroblasts / Q000378:metabolism; D055785:Gene Knockdown Techniques; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology*; D023822:Tissue Engineering; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020725:ral GTP-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D015820:Cadherins; C470182:EXOC2 protein, human; C480857:EXOC8 protein, human; C483163:Ralb protein, human; D033921:Vesicular Transport Proteins; D017228:Hepatocyte Growth Factor; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins