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Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
EGFR-mediated local invasiveness and response to Cetuximab in head and neck cancer
Jiefu Zhou1,2,3,4, Min He1, Qiong Zhao1
1Department of Otorhinolaryngology, LMU University Hospital, LMU Munich, Munich, Germany.
Background:
Recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC) is a severe, frequently lethal condition. Oncogene addiction to epidermal growth factor receptor (EGFR) is a hallmark of HNSCC, but the clinical efficacy of EGFR-targeted therapies remains low. Understanding molecular networks governing EGFR-driven progression is paramount to the exploration of (co)-treatment targets and predictive markers.
Methods:
We performed function-based mapping of differentially expressed genes in EGFR-mediated local invasion (fDEGs) using photoconvertible tracers and RNA-sequencing (RNA-seq) in a cellular 3D-model.
Results:
Upon alignment with public single-cell RNA-seq (scRNA-seq) datasets and HNSCC-specific regulons, a gene regulatory network of local invasion (invGRN) was inferred from gene expression data, which was overrepresented in budding tumors. InvGRN comprises the central hubs inhibin subunit beta alpha (INHBA) and snail family transcriptional repressor 2 (SNAI2), and druggable fDEGs integrin subunit beta 4 (ITGB4), laminin 5 (LAMB3/LAMC2), and sphingosine kinase 1 (SPHK1). Blockade of INHBA repressed local invasion and was reverted by activin A, laminin 5, and sphingosine-1-phosphate, demonstrating a functional interconnectivity of the invGRN. Epithelial-to-mesenchymal transition (EMT) of malignant cells and the invGRN are induced by newly defined EGFR-activity subtypes with prognostic value that are promoted by amphiregulin (AREG) and epiregulin (EREG). Importantly, co-inhibition of SPHK1 showed synthetic effects on Cetuximab-mediated invasion blockade and high expression of selected fDEGs was associated with response to Cetuximab in patient-derived xenotransplantation (PDX) and R/M-HNSCC patients.
Conclusions:
We describe an actionable network of EGFR-mediated local invasion and define druggable effectors with predictive potential regarding the response of R/M-HNSCC to Cetuximab.
Insights
Researchers identified a gene network driving head and neck cancer invasion, revealing new targets for EGFR-inhibitor therapies. Blocking key molecules like INHBA and SPHK1 shows promise for treating recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC).
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC) presents a significant clinical challenge with limited efficacy of current epidermal growth factor receptor (EGFR)-targeted therapies.
- Understanding the molecular mechanisms driving EGFR-dependent tumor progression is crucial for identifying effective co-treatment strategies and predictive biomarkers.
Purpose of the Study:
- To elucidate the molecular networks governing EGFR-mediated local invasion in head and neck squamous cell carcinoma (HNSCC).
- To identify actionable targets and predictive markers for R/M-HNSCC treatment, particularly in response to EGFR inhibitors like Cetuximab.
Main Methods:
- Function-based mapping of differentially expressed genes (fDEGs) involved in EGFR-mediated local invasion using photoconvertible tracers and RNA-sequencing (RNA-seq) in a 3D cell model.
- Inference of a gene regulatory network of local invasion (invGRN) by integrating gene expression data with public single-cell RNA-seq (scRNA-seq) datasets and HNSCC-specific regulons.
Main Results:
- The inferred invGRN, overrepresented in budding tumors, identified inhibin subunit beta alpha (INHBA) and snail family transcriptional repressor 2 (SNAI2) as central hubs.
- Druggable targets within the invGRN include integrin subunit beta 4 (ITGB4), laminin 5 (LAMB3/LAMC2), and sphingosine kinase 1 (SPHK1).
- Functional experiments confirmed the interconnectivity of the invGRN, with INHBA blockade inhibiting invasion, and co-inhibition of SPHK1 synergizing with Cetuximab to block invasion. Novel EGFR-activity subtypes associated with epithelial-to-mesenchymal transition (EMT) and prognostic value were identified, promoted by amphiregulin (AREG) and epiregulin (EREG).
Conclusions:
- A druggable network regulating EGFR-mediated local invasion in HNSCC has been characterized.
- Specific molecular effectors within this network demonstrate potential as predictive biomarkers for Cetuximab response in R/M-HNSCC patients.
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