Analysis of head and neck carcinoma progression reveals novel and relevant stage-specific changes associated with immortalisation and malignancy

Veeramachaneni, Ratna; Walker, Thomas D. J.; Weck, Antoine de; Revil, Timothée; Badescu, Dunarel; O’Sullivan, James; Higgins, Catherine L.; Elliott, Louise; Liloglou, Triantafillos; Risk, Janet M.; Shaw, Richard; Hampson, Lynne; Hampson, Ian N.; Dearden, Simon; Woodwards, R.T.; Prime, Stephen S.; Hunter, Keith; Parkinson, Eric Kenneth; Ragoussis, Jiannis; Thakker, Nalin

doi:10.1101/365205

Cited by 4 publications

(5 citation statements)

References 66 publications

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“…Three of the other genes with more mutations, IGSF3 (1194 aa) also appear in the eleven tumors, while PABPC3 (631 aa) and TEKT4 (435 aa) occur in seven (out of eleven) tumors. Although these three genes have been related to tumor formation, their roles may be indirect [28][29][30][31] . Two other genes, TAS2R30…”

Section: Mutated Cancer Genes' Analysesmentioning

confidence: 99%

Mutational signatures and increased retrotransposon insertions in Xeroderma Pigmentosum variant skin tumors

Corradi

Vilar

Buzatto

et al. 2022

Preprint

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Xeroderma Pigmentosum variant (XP-V) is an autosomal recessive disease with an increased risk to develop cutaneous neoplasms in sunlight exposed regions. These cells are deficient in the translesion synthesis DNA polymerase eta. Eleven skin tumors from a genetic cluster of XP-V patients had their exome sequenced. Mutational signatures identified for most tumors were related to ultraviolet exposure, such as C>T transitions targeted to pyrimidine dimers. However, four samples carry different mutational signatures, with C>A mutations associated with tobacco usage. Basal cell carcinomas showed a distinct C>A mutation spectra reflecting a novel mutational signature. Higher levels for retroposon insertions were detected in the XP-V tumors, compared to non-XP skin tumors. The results reveal other possible causes for XP-V tumors and the involvement of polymerase eta in suppressing retrotransposition. The expected high mutation burden, found in most of these tumors, renders these XP patients good candidates for immunotherapy with checkpoint blockers.

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Section: Mutated Cancer Genes' Analysesmentioning

confidence: 99%

Mutational signatures and increased retrotransposon insertions in Xeroderma Pigmentosum variant skin tumors

Corradi

Vilar

Buzatto

et al. 2022

Preprint

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“…Cooperative mechanisms linked to the breakdown of the OE basal layer such as the activation of p16 INK4A may guide replicative senescence, limiting cellular migration and proliferation while retaining normal growth and differentiation characteristics [21][22][23][24]. In the event of chronic insult, stem cell activation persists in a state that is prone to acquire genetic/epigenetic alterations, which can eventually lead to senescence bypass and oncogenic transformation [25][26][27][28]. Hence, following the damage repair of oral tissue, the differentiation of committed progenitor cells is crucial for tissue remodelling and the prevention of oral diseases and carcinogenesis.…”

Section: Damage-induced Stem Cell Activationmentioning

confidence: 99%

“…In recent years, it has become clear that the prognostic value of EGFR overexpression or increased gene copy number does not correlate with Cetuximab response due to common alterations downstream of EGFR [103]. Somatic mutations, genetic and epigenetic alterations have been shown to drive senescence bypass, proliferation, continuous cancer cell survival and OSCC treatment resistance [25,104]. Such mechanisms render most OSCC patients difficult to cure and emphasise the urgent need to identify additional strategies to enhance therapy response [105].…”

Section: Targeted Therapy Against Osccmentioning

confidence: 99%

The Balance between Differentiation and Terminal Differentiation Maintains Oral Epithelial Homeostasis

Bai

Boath

White

et al. 2021

Cancers

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The oral epithelium is one of the fastest repairing and continuously renewing tissues. Stem cell activation within the basal layer of the oral epithelium fuels the rapid proliferation of multipotent progenitors. Stem cells first undergo asymmetric cell division that requires tightly controlled and orchestrated differentiation networks to maintain the pool of stem cells while producing progenitors fated for differentiation. Rapidly expanding progenitors subsequently commit to advanced differentiation programs towards terminal differentiation, a process that regulates the structural integrity and homeostasis of the oral epithelium. Therefore, the balance between differentiation and terminal differentiation of stem cells and their progeny ensures progenitors commitment to terminal differentiation and prevents epithelial transformation and oral squamous cell carcinoma (OSCC). A recent comprehensive molecular characterization of OSCC revealed that a disruption of terminal differentiation factors is indeed a common OSCC event and is superior to oncogenic activation. Here, we discuss the role of differentiation and terminal differentiation in maintaining oral epithelial homeostasis and define terminal differentiation as a critical tumour suppressive mechanism. We further highlight factors with crucial terminal differentiation functions and detail the underlying consequences of their loss. Switching on terminal differentiation in differentiated progenitors is likely to represent an extremely promising novel avenue that may improve therapeutic interventions against OSCC.

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“…HNSCCs arise from the mucosal epithelium of the oral cavity, larynx, and pharynx [1]. The prevalence of HNSCCs is nowadays increasing, while the survival rates and prognosis remain poor despite the various treatment options for these malignancies [2,3]. As treatment differs between patients, disease stages, and regional involvement, chemotherapy has long been used alone or in com-Pharmacology 2023;108:90-100 DOI: 10.1159/000527082 bination with other treatment modalities [1].…”

Section: Introductionmentioning

confidence: 99%

Recapitulating the Pharmacological Interactions of Cetuximab with Sunitinib and Cisplatin in Head and Neck Carcinoma Cells in vitro

et al. 2022

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Introduction: Cisplatin is extensively used in the treatment of head and neck carcinomas. Cetuximab combination therapy is employed in recurrent and metastatic settings. Sunitinib showed positive results in the treatment of head and neck carcinomas, both as monotherapy or in combination with cetuximab. Nonetheless, the mechanism governing these pharmacological interactions is largely unresolved. This study investigates the impact of cetuximab on the cytotoxicity of cisplatin and sunitinib using cells representative of head and neck carcinoma and the oral epithelium. Methods: The uptake and efflux activities of cells were determined using the prototypical fluorescent substrates 4-[4-[dimethylamino]styryl)-1-methyl pyridinium iodide, Hoechst 33342, and calcein-AM in the presence or absence of specific inhibitors in cells pretreated with cetuximab. The expression of key uptake and efflux drug transporters was analyzed using qPCR and immunofluorescence. Cisplatin and sunitinib cytotoxicities after cetuximab pretreatment were evaluated using the PrestoBlue viability assay. Results: Both tumor and nontumor cells showed significant active drug transport activity. Cetuximab substantially deregulated the expression of key transporters involved in drug resistance in head and neck cancer cells. Transporter expression in the nontumor cell was unaffected. Upon cetuximab pretreatment, the half maximal effective toxic concentration of cisplatin was reduced by 0.75-fold and sunitinib by 0.82-fold in cancer cells. Nontumor cells were not sensitive to cisplatin or sunitinib under the conditions tested. Conclusion: Cetuximab regulates the expression and activity of key membrane drug transporters in head and neck cancer cells, involved in drug resistance. The deregulation of the transport mechanism behind cisplatin and sunitinib uptake reverses drug resistance and enhances the cytotoxicity of both drugs.

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Analysis of head and neck carcinoma progression reveals novel and relevant stage-specific changes associated with immortalisation and malignancy

Cited by 4 publications

References 66 publications

Mutational signatures and increased retrotransposon insertions in Xeroderma Pigmentosum variant skin tumors

Mutational signatures and increased retrotransposon insertions in Xeroderma Pigmentosum variant skin tumors

The Balance between Differentiation and Terminal Differentiation Maintains Oral Epithelial Homeostasis

Recapitulating the Pharmacological Interactions of Cetuximab with Sunitinib and Cisplatin in Head and Neck Carcinoma Cells in vitro

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