Oral mucosa organoids as a potential model for personalized therapies
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PROVIDER: EGAS00001003628 | EGA |
REPOSITORIES: EGA
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Project description:Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive cancer, with limited therapeutic options and a high mortality rate, primarily due to metastasis and recurrence. Tumor-stroma interactions, and namely cancer-associated fibroblasts (CAFs), are pivotal in shaping HNSCC progression. CAFs remodel the extracellular matrix (ECM) and secrete factors and vesicles that promote tumor growth and metastasis. The interplay between autophagy and endosomal/exosomal pathways has been suggested to regulate cellular secretory functions, but their potential involvement in HNSCC progression remains poorly understood. Since we have recently uncovered Gαq as a key modulator of autophagy, we have investigated the impact of Gαq loss on fibroblast functionality and on its crosstalk with oral HNSCC cells. We report that the absence of Gαq rewires murine embryonic fibroblasts towards CAF-like traits, leading to an increased pro-tumorigenic capacity of co-cultured human oral cancer cells through enhanced collagen I deposition and ECM remodeling. Strikingly, fibroblasts lacking Gαq display a shift the balance of intracellular trafficking, degradative and secretory pathways. Exosomes released from Gαq-deficient fibroblasts show a marked enrichment in tumor-growth factor receptors and can facilitate aberrant tumor growth of HNSCC cells. Gαq-silenced fibroblasts promote the formation of "railroad-tracks" structures around HNSCC cells, enhancing their migratory and invasive capabilities both in vitro and in vivo, and reduced Gαq expression in human HNSCC CAFs correlates with enhanced tumor progression. Overall, our data put forward Gαq as a key regulator of the HNSCC tumor microenvironment by modulating fibroblast plasticity and functionality.
2026-03-27 | PXD061641 | Pride
Project description:Serum-driven responses, many of which are related to wound healing, are potentially deregulated in cancer development and associated genomic alterations might have prognostic value. The current study assessed fetal bovine serum-induced transcriptomic changes for clinical relevance in head and neck squamous cell carcinoma (HNSCC) using oral keratinocyte models otherwise routinely cultured without serum, including normal keratinocytes (NOK) and the transformed keratinocyte lines SVpgC2a, SqCC/Y1 and LK0412. Bioinformatics-driven analysis of gene expression implicated primarily serum-induced terminal differentiation in NOK including alterations in 99 genes, 13 gene ontology-categories and 6 molecular networks and involvement of 7 key regulator genes. Compared to NOK, the transformed lines expressed around 3-fold lower numbers of differently expressed transcripts, unique sets of gene ontologies, molecular networks and key regulator genes for each line, and consistent absence of terminal differentiation markers. Assessment of the complete in vitro/serum exposure-derived set of differentially expressed genes (totally 180 genes) relative a clinical, information-rich HNSCC data set identified 17 survival-associated genes of which only 12 had previous association to HNSCC. Multi-step validation of the survival-associated genes relative to several independent tumor data sets, including in the Human Gene Expression Map and Human Protein Atlas databases, confirmed novel association to HNSCC for genes COTL1 and INSIG1 and novel poor outcome prediction for the genes CUL4B and PDGFRL. The definition of normal and aberrant serum responses in keratinocyte models therefore coupled new genes to HNSCC including with relevance to prognosis. Analysis of gene expression changes in serum-exposed normal and transformed cells relative the respective un-exposed states. Significantly differentially expressed genes were next assessed by bioinformatics processing using Gene Ontology categories and network analyses. Findings were also validated relative independent HNSCC data sets as well as transcriptomics and proteomics databases.
2014-01-01 | E-GEOD-39376 | biostudies-arrayexpress
Project description:Serum-driven responses, many of which are related to wound healing, are potentially deregulated in cancer development and associated genomic alterations might have prognostic value. The current study assessed fetal bovine serum-induced transcriptomic changes for clinical relevance in head and neck squamous cell carcinoma (HNSCC) using oral keratinocyte models otherwise routinely cultured without serum, including normal keratinocytes (NOK) and the transformed keratinocyte lines SVpgC2a, SqCC/Y1 and LK0412. Bioinformatics-driven analysis of gene expression implicated primarily serum-induced terminal differentiation in NOK including alterations in 99 genes, 13 gene ontology-categories and 6 molecular networks and involvement of 7 key regulator genes. Compared to NOK, the transformed lines expressed around 3-fold lower numbers of differently expressed transcripts, unique sets of gene ontologies, molecular networks and key regulator genes for each line, and consistent absence of terminal differentiation markers. Assessment of the complete in vitro/serum exposure-derived set of differentially expressed genes (totally 180 genes) relative a clinical, information-rich HNSCC data set identified 17 survival-associated genes of which only 12 had previous association to HNSCC. Multi-step validation of the survival-associated genes relative to several independent tumor data sets, including in the Human Gene Expression Map and Human Protein Atlas databases, confirmed novel association to HNSCC for genes COTL1 and INSIG1 and novel poor outcome prediction for the genes CUL4B and PDGFRL. The definition of normal and aberrant serum responses in keratinocyte models therefore coupled new genes to HNSCC including with relevance to prognosis.
2014-01-01 | GSE39376 | GEO
Project description:To identify the activated tyrosine kinase signaling pathways in HNSCC, we carried out phosphotyrosine profiling using a panel of HNSCC cell lines compared to a normal oral keratinocyte. A total of 61 unique phosphosites were identified across these cell lines. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) was one of the kinases hyperphosphorylated at Y321 in all the HNSCC cell lines compared to the normal oral cell line OKF6/TERT1. Inhibition of DYRK1A using its specific siRNA and inhibitor resulted in a decrease in the invasion and colony formation ability of the HNSCC cell lines. Further, the treatment of mice bearing HNSCC xenograft tumors with DYRK1A inhibitor (harmine) showed regression of tumor growth. Our results demonstrate that DYRK1A could be a novel therapeutic target in HNSCC.
2018-10-24 | PXD002132 | Pride
Project description:Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with limited therapeutic options and poor outcomes due to metastasis. A major driver of tumor progression is the tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), which remodel the extracellular matrix and secrete pro-tumorigenic signals. Emerging evidence suggests that autophagy and vesicle trafficking pathways regulate these secretory functions, though their role in HNSCC remains unclear. Building on our discovery of Gαq as a central autophagy regulator, we investigated how its absence reshapes fibroblast behavior and modulates crosstalk with oral HNSCC cells. Our findings demonstrate that loss of Gαq reprograms murine fibroblasts into a CAF-like phenotype, in part through deregulated intracellular trafficking and increased ceramide accumulation. Gαq-deficient fibroblasts display increased collagen I deposition, ECM remodeling, and a shift toward secretory activity. Their exosomes, enriched in tumor-promoting growth factor receptors, suppress Caveolin 1 expression in tumor cells and induce an EMT-like phenotype that fuels aberrant HNSCC growth. In co-culture and in vivo, Gαq-silenced fibroblasts assemble into “railroad-track” structures that guide cancer cell migration and invasion. Reduced Gαq expression in human fibroblasts recapitulate these features underscoring a conserved mechanism of stromal activation. Overall, Gαq emerges as a key regulator of fibroblast plasticity and tumor-stroma interactions in HNSCC progression.
2026-03-28 | GSE312614 | GEO
Project description:Background: The epigenetic consequences of ionizing radiation (IR), particularly its effects on DNA methylation, remain poorly understood. Here, we investigated whether IR induces genome-wide DNA methylation changes in OSCC cells and examined whether IR-induced hypomethylated candidate genes correspond to epigenetically silenced loci in oral cancer patient tumors, and whether their methylation status influences clinical outcomes. Methods: OSCC cells were treated with IR or 5-aza-2'-deoxycytidine (5-aza-dC) and subjected to genome-wide DNA methylation profiling using the Illumina HumanMethylationEPIC BeadChip. Candidate hypomethylated genes were validated by qRT-PCR and quantitative methylation-specific PCR (qMSP). DNMT1 promoter occupancy was assessed by chromatin immunoprecipitation (ChIP). Clinical relevance was evaluated using the TCGA-HNSCC dataset. Results: IR significantly reduced DNMT1 and DNMT3b protein levels in OSCC cells, indicating IR-induced global DNA hypomethylation. Genome-wide profiling identified three candidate genes, MLPH, BMP4, and MYO5A, showing concordant promoter demethylation and transcriptional upregulation following IR treatment, with ChIP analysis confirming reduced DNMT1 occupancy at their promoters. Importantly, TCGA-HNSCC analysis revealed that BMP4 and MLPH are hypermethylated and transcriptionally silenced in untreated HNSCC tumors, a finding mechanistically complementary to our experimental data, suggesting that IR reverses tumor-associated epigenetic silencing through DNMT1-mediated passive demethylation. Consistently, BMP4 hypermethylation was associated with poor overall survival, and BMP4-hypermethylated patients receiving radiotherapy survived longer than those receiving chemotherapy. Conclusions: This study provides the first evidence that IR induces genome-wide DNA hypomethylation in OSCC through DNMT1 and DNMT3b downregulation, reactivating epigenetically silenced genes including MLPH, BMP4, and MYO5A. These findings suggest that IR-induced epigenetic reactivation of tumor-silenced genes may represent a clinically meaningful mechanism of radiotherapy response, and that BMP4 methylation status may serve as a potential predictive biomarker in oral cancer.
2026-07-10 | GSE335152 | GEO
Project description:DNA methylation profiling of heterogeneous head and neck squamous cell carcinoma (HNSCC) cohorts has been reported to predict patient outcome. We investigated if a prognostic DNA methylation profile could be found in tumour tissue from a single uniform subsite, the oral tongue. The methylation status of 83 comprehensively annotated oral tongue squamous cell carcinoma (OTSCC) formalin-fixed paraffin-embedded (FFPE) samples from a single institution were examined with the Illumina HumanMethylation450K (HM450K) array.
2016-07-18 | GSE79556 | GEO
Project description:Purpose: Advanced high-grade gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) are highly aggressive and heterogeneous epithelial malignancies with poor clinical outcomes. No therapeutic predictive biomarkers exist and representative preclinical models to study their biology are missing. Patient-derived (PD) tumoroids may enable fast ex vivo pharmacotyping and provide subsidiary biological information for more personalized therapy strategies in individual patients. Experimental Design: PD tumoroids were established from rare biobanked surgical resections of advanced high-grade GEP-NEN patients. Using targeted in vitro pharmacotyping and next-generation sequencing of patient samples and matching PD tumoroids, we profiled individual patients and compared treatment-induced molecular stress response and in vitro drug sensitivity to the clinical therapy response. Results: We demonstrate high success rates in culturing PD tumoroids of high-grade GEP-NENs within clinically meaningful timespans. PD tumoroids recapitulate biological key features of high-grade GEP-NEN and mimic clinical response to cisplatin and temozolomide in vitro. Moreover, investigating treatment-induced molecular stress responses in PD tumoroids in silico, we discovered and functionally validated Lysine demethylase 5A (KDM5A) and interferon-beta (IFNB1) as two vulnerabilities that act synergistically in combination with cisplatin and may present novel therapeutic options in high-grade GEP-NENs. Conclusion: Patient-derived tumoroids from high-grade GEP-NENs represent a relevant model to screen drug sensitivities of individual patients within clinically relevant timespans and provide novel functional insights into drug-induced stress responses. Clinical patient response to standard-of-care chemotherapeutics matches with drug sensitivities of PD tumoroids. Together, our findings provide a functional precision oncology approach for gathering patient-centered subsidiary treatment information that will potentially increase therapeutic opportunities in the framework of personalized medicine.
2024-03-01 | GSE213504 | GEO
Project description:DNA methylation profiling of heterogeneous head and neck squamous cell carcinoma (HNSCC) cohorts has been reported to predict patient outcome. We investigated if a prognostic DNA methylation profile could be found in tumour tissue from a single uniform subsite, the oral tongue. The methylation status of 83 comprehensively annotated oral tongue squamous cell carcinoma (OTSCC) formalin-fixed paraffin-embedded (FFPE) samples from a single institution were examined with the Illumina HumanMethylation450K (HM450K) array. 83 FFPE primary OTSCC tumour samples were analysed in one experimental run.
2016-07-18 | E-GEOD-79556 | biostudies-arrayexpress
Project description:Human papillomavirus-negative head and neck squamous cell carcinoma (HNSCC) is a highly malignant disease with high death rates that have remained substantially unaltered for decades. Therefore, new treatment approaches are urgently needed. Human papillomavirus-negative tumors harbor areas of terminally differentiated tissue that are characterized by cornification. Dissecting this intrinsic ability of HNSCC cells to irreversibly differentiate into non-malignant cells may have striking tumor-targeting potential.
2024-08-08 | GSE273699 | GEO