Abstract
Gallbladder carcinoma (GBC) exhibits poor prognosis due to local recurrence, metastasis, and resistance to targeted therapies. Using clinicopathological analyses of GBC patients along with molecular in vitro and tumor in vivo analysis of GBC cells, we showed that reduction of Dsg2 expression was highly associated with higher T stage, more perineural, and lymphatic invasion. Dsg2-depleted GBC cells exhibited significantly enhanced proliferation, migration, and invasiveness in vitro and tumor growth and metastasis in vivo through Src-mediated signaling activation. Interestingly, Dsg2 binding inhibited Src activation, whereas its loss activated cSrc-mediated EGFR plasma membrane clearance and cytoplasmic localization, which was associated with acquired EGFR-targeted therapy resistance and decreased overall survival. Inhibition of Src activity by dasatinib enhanced therapeutic response to anti-EGFR therapy. Dsg2 status can help stratify predicted patient response to anti-EGFR therapy and Src inhibition could be a promising strategy to improve the clinical efficacy of EGFR-targeted therapy.
Highlights
Gallbladder carcinoma (GBC) is a rare neoplasm, but the most common malignancy of the biliary tract
Previous clinical trials with epidermal growth factor receptor (EGFR)-targeted agents plus standard chemotherapy did not provide any clinical benefits for patients with GBC, even though EGFR is frequently overexpressed in GBC and is critical for gallbladder epithelial cell growth and proliferation [5, 8, 9]
We demonstrated for the first time that the desmosomal component Dsg2 played a tumor-suppressive role in GBC cells, as its loss-induced key biological activities of cells, including proliferation, motility, invasion, and transendothelial migration in vitro, as well as GBC tumor growth and metastasis in vivo
Summary
Gallbladder carcinoma (GBC) is a rare neoplasm, but the most common malignancy of the biliary tract. The current standard first-line therapy for patients with advanced biliary tract cancer (BTC), including GBC, is a combination of gemcitabine plus platinum-based agents. Oncogenic KRAS mutations predict the lack of efficacy of cetuximab when combined with chemotherapy [10]. Such findings might not directly translate to BTC cases, as no correlation was found between the mutation status and clinical outcomes [9]. Identifying the regulators inducing the aggressive features of BTC and elucidating the underlying molecular events of BTC progression are necessary for developing new therapeutic strategies In this context, it is critical to understand the molecular carcinogenesis and key molecular pathways associated with GBC to establish individualized targeted molecular therapies
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