Interplay between Partial EMT and Cisplatin Resistance as the Drivers for Recurrence in HNSCC

Abstract

This study aims to investigate the role of partial epithelial to mesenchymal transition (pEMT)-related proteins in modulating Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC). SCC-25 cells were pre-treated with TGF-beta1 followed by transient Krüppel-like Factor 4 (KLF4)-overexpression and Cisplatin treatment. Cell growth, cell morphological changes and cell migration were assessed using Juli BR live cell video-microscopy. In addition, Ki-67 and Slug immunostaining and follow-up image cytometric analysis of primary and recurrent HNSCC tumors were performed to evaluate the proliferation index (PI) and the EMT-like phenotype. We observed that proliferating and Slug-positive tumor cells expand after therapy in HNSCC. Subsequently, protein analysis revealed the stabilization of Slug, upregulation of Vimentin and phospho-p38 (p-p38) in Cisplatin-resistant SCC-25 cells. Moreover, KLF4-overexpression contributed to Cisplatin sensitivity by reduction of Slug at the protein level. This work strongly suggests that an pEMT-like pathway is activated in recurrent and Cisplatin-resistant HNSCC. Finally, stable KLF4-overexpression might sensitize HNSCC tumor cells for Cisplatin treatment.

Natural killer cell‐based signature: Prognostic analysis in head and neck squamous cell carcinoma

“…Chen et al 50 found that the interaction between CCL21 and CCR7 could significantly promote EMT process and tumor stemness of HNSC cells through JAK2/STAT3 signaling. Ingruber et al 51 discovered that the interaction between EMT and cisplatin resistance could act as a driver of HNSC recurrence. Yu et al 52 found that the IGF2BP2, a m6A reader, could promote the lymphatic metastasis and MET process of HNSC.…”

“…Ingruber et al 51 discovered that the interaction between EMT and cisplatin resistance could act as a driver of HNSC recurrence. Yu et al 52 found that the IGF2BP2, a m6A reader, could promote the lymphatic metastasis and MET process of HNSC.…”

Cytotoxic response of tumor-infiltrating lymphocytes of head and neck cancer slice cultures under mitochondrial dysfunction

“…With the simultaneous use of differently labeled antibodies, multiplex cytometry is possible, allowing a differentiated analysis of the phenotype, spatial distribution, and activation of cells ( 24 ) in the TME. Recent imaging cytometric techniques allow automatic differentiation between tumor cell aggregates and tumor stroma in HNSCC ( 25 ).…”

p38 Mitogen-Activated Protein Kinase Inhibition of Mesenchymal Transdifferentiated Tumor Cells in Head and Neck Squamous Cell Carcinoma

“…Poor survival can be attributed to the high frequency of recurrence and second primary tumor, to tumor metastasis and radiochemotherapy (RCT) resistance [1,2]. Hypoxic conditions, cellular stress, mitochondrial dysfunction [3], and, in particular, the reversible process of partial epithelial to mesenchymal transition (pEMT) precondition tumor cells to therapy resistance [4][5][6]. Both applied RCT and pEMT processes might activate and stabilize the pro-EMT-transcription factor Slug and induce and sustain p38 mitogen-activated protein kinase (MAPK) phosphorylation [4].…”

“…During pEMT, polarized and differentiated epithelial cells acquire a reversible mesenchymal phenotype [6]; they underlie changes in morphology and give up their epithelial features and gene expression profile [7,8]. Cells undergoing pEMT release their lateral cell-cell contacts, their connection to the basal substrate, become motile, achieve collective invasion [4,6], and enforce stronger interaction with the extracellular matrix. These are typical features of the nonpolar mesenchymal phenotype [9].…”