Loss of desmoglein-2 promotes gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation

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.

Deep Proteomic Analysis on Biobanked Paraffine-Archived Melanoma with Prognostic/Predictive Biomarker Read-Out

“…Divergent results have been found concerning the desmocolllin-2 role in metastasis. Evidence suggests that the reduction in the expression of this protein promotes cellular migration and tumor invasion [ 35 , 36 , 37 ], while other studies affirm that the upregulation of desmoglein 2 promotes vasculogenic mimicry and metastatic spread in melanoma [ 38 ]. On the other hand, the decline of proteins associated with the hemidesmosome components was also related to metastasis progression and poor clinical outcomes [ 39 ], and it correlates with our results since we have seen the downregulation of these proteins in sample cluster 4 with poor disease-free survival.…”

Nanoparticle-Based RNAi Therapeutics Targeting Cancer Stem Cells: Update and Prospective

“…Besides, induction of Dickkopf-related protein 1 (DKK1), an endogenous inhibitor of LRP5 and LRP6, results in the delay of cancer progression [42,43]. 1 Wnt ligand secretion mediator; 2 C-X-C motif chemokine receptor 4; 3 Avanti polar lipids liposome; 4 Hyaluronic acid-chitosan nanoparticles; 5 Hyaluronic acid/protamine sulfate interpolyelectrolyte complex; 6 Poly (lactic-co-glycolic acid) nanoparticles; 7 Mixed nanosized polymeric micelles; 8 NCK associated protein 1; 9 Phosphatidylinositol-4-phosphate 5-kinase type 1 γ; 10 ATPase family AAA domain containing 2. As a result, small-molecule inhibitors and antibodies targeting these critical components of the Wnt pathway were rapidly developed, but have not yet demonstrated sufficient effectiveness or are still being investigated in small-scale clinical trials.…”

“…Most patients who die from cancer eventually develop resistance to multiple therapeutic modalities [5]. Although new therapeutic strategies, including targeted therapies and immunotherapy, have been proposed [6,7], cancer resistance continues to emerge by similar mechanisms [8][9][10]. As a result, several approaches aimed at combating unique pathways of drug resistance emerged fast and contributed significantly to improved prognosis [11].…”

Long Non-Coding RNA Myosin Light Chain Kinase Antisense 1 Plays an Oncogenic Role in Gallbladder Carcinoma by Promoting Chemoresistance and Proliferation

“…Gallbladder carcinoma (GBC) has a poor prognosis due to local recurrence, metastasis, and resistance to targeted therapies. 1 Gemcitabine is widely used as the first-line treatment in locally advanced and metastatic GBC. 2 However, patient prognosis is usually limited by natural and acquired chemotherapy resistance.…”