Charbel Darido

Metastasis presents a significant challenge in head and neck squamous cell carcinoma (HNSC), profoundly impacting patient morbidity and mortality. This proof‐of‐concept study establishes patient‐derived orthotopic xenografts (PDOXs) as an advanced preclinical model to investigate and address metastatic HNSC. Indeed, PDOXs demonstrate noteworthy histopathological and molecular fidelity to primary HNSC tumours. Contrary to the traditional subcutaneous xenografts, PDOXs authentically replicate local lymph node metastasis, mirroring the intricate site‐specific cancer–stroma interaction and the disease progression in patients. Furthermore, genomic and transcriptomic analyses underscore the genetic accuracy and heightened resemblance of PDOXs to patient tumours. Notably, nuclear factor kappa‐B (NF‐κB)‐signalling‐induced inflammation emerges as a key driver of the metastatic process, unveiling an inflammatory signature with potential implications as a prognostic marker and therapeutic target. These findings underscore the pivotal role of the PDOX model in capturing the complex biology of HNSC, providing insights for precision‐targeted therapies and enhancing patient outcomes.

The World Health Organisation recognised human papillomavirus (HPV) as the cause of multiple cancers, including head and neck cancers. HPV is a double-stranded DNA virus, and its viral gene expression can be controlled after infection by cellular and viral promoters. In cancer cells, the HPV genome is detected as either integrated into the host genome, episomal (extrachromosomal), or a mixture of integrated and episomal. Viral integration requires the breakage of both viral and host DNA, and the integration rate correlates with the level of DNA damage. Interestingly, patients with HPV-positive head and neck cancers generally have a good prognosis except for a group of patients with fully integrated HPV who show worst clinical outcomes. Those patients present with lowered expression of viral genes and limited infiltration of cytotoxic T cells. An impediment to effective therapy applications in the clinic is the sole testing for HPV positivity without considering the HPV integration status. This review will discuss HPV integration as a potential determinant of response to therapies in head and neck cancers and highlight to the field a novel therapeutic avenue that would reduce the cancer burden and improve patient survival.

In heterogeneous head and neck cancer (HNC), subtype-specific treatment regimens are currently missing. An integrated analysis of patient HNC subtypes using single-cell sequencing and proteome profiles reveals an epithelial-mesenchymal transition (EMT) signature within the epithelial cancer-cell population. The EMT signature coincides with PI3K/mTOR inactivation in the mesenchymal subtype. Conversely, the signature is suppressed in epithelial cells of the basal subtype which exhibits hyperactive PI3K/mTOR signalling. We further identify YBX1 phosphorylation, downstream of the PI3K/mTOR pathway, restraining basal-like cancer cell proliferation. In contrast, YBX1 acts as a safeguard against the proliferation-to-invasion switch in mesenchymal-like epithelial cancer cells, and its loss accentuates partial-EMT and in vivo invasion. Interestingly, phospho-YBX1 that is mutually exclusive to partial-EMT, emerges as a prognostic marker for overall patient outcomes. These findings create a unique opportunity to sensitise mesenchymal cancer cells to PI3K/mTOR inhibitors by shifting them towards a basal-like subtype as a promising therapeutic approach against HNC.

Breakthrough research in the field of immune checkpoint inhibitors and the development of a human papilloma virus vaccine triggered a plethora of research in the field of cancer immunotherapy. Both had significant effects on the treatment of head and neck squamous cell carcinoma. The advent of preclinical models and multidisciplinary approaches including bioinformatics, genetic engineering, clinical oncology, and immunology helped in the development of tumour-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T-cell therapy. Here, we discuss different immunotherapies such as adoptive T-cell transfer, immune checkpoint inhibitors, interleukins, and cancer vaccines for the treatment of head and neck cancer. This review showcases the intrinsic relation between the understanding and implementation of basic biology and clinical practice. We also address potential limitations of each immunotherapy approach and the advantages of personalized immunotherapy. Overall, the aim of this review is to encourage further research in the field of immunotherapy for head and neck cancer.

Squamous cell carcinomas (SCCs) are cancers of epithelial cells lining the aerodigestive and genitourinary tract

Background: Aberrant proliferation is a hallmark of cancer. Cellular proliferation mechanisms and various cytokines contribute to the progression of cancer. The tumor suppressor protein Suppressor of Cytokine Signalling 3 (SOCS3), which acts via the JAK/STAT pathway, have a role in the progression of cancer. Aim: To explore the role of SOCS3 in all the hallmarks of cancer. To exhibit SOCS3 action on proliferation pathways and immune aspect affecting cancer progression. Methods: The PubMed database was searched using the keywords proliferation, SOCS3, JAK/STAT, interleukins, and tumor suppressor. Articles relevant to SOCS3 were considered for this review. Results: In this review, we have illustrated the dual action of SOCS3, which inhibits various proliferative mechanisms and affects certain interleukins that counterbalance the progression of cancer. In addition, SOCS3 affects all the hallmarks of cancer. Conclusion: We hope that this review will stimulate further investigation of SOCS3, which has the potential to become a new target for the pharmacological treatment of various cancers in the future.

Grainyhead-like (GRHL) factors are essential, highly conserved transcription factors (TFs) that regulate processes common to both natural cellular behaviours during embryogenesis, and de-regulation of growth and survival pathways in cancer. Serving to drive the transcription, and therefore activation of multiple co-ordinating pathways, the three GRHL family members (GRHL1-3) are a critical conduit for modulating the molecular landscape that guides cellular decision-making processes during proliferation, epithelial-mesenchymal transition (EMT) and migration. Animal models and in vitro approaches harbouring GRHL loss or gain-of-function are key research tools to understanding gene function, which gives confidence that resultant phenotypes and cellular behaviours may be translatable to humans. Critically, identifying and characterising the target genes to which these factors bind is also essential, as they allow us to discover and understand novel genetic pathways that could ultimately be used as targets for disease diagnosis, drug discovery and therapeutic strategies. GRHL1-3 and their transcriptional targets have been shown to drive comparable cellular processes in Drosophila, C. elegans, zebrafish and mice, and have recently also been implicated in the aetiology and/or progression of a number of human congenital disorders and cancers of epithelial origin. In this review, we will summarise the state of knowledge pertaining to the role of the GRHL family target genes in both development and cancer, primarily through understanding the genetic pathways transcriptionally regulated by these factors across disparate disease contexts.

Introduction: Transient receptors are related to oral cancer pain. Previously capsaicin (TRPV1 agonist) was shown to induce cell death in oral cancer cells. We hypothesised that these receptors are present in oral cancer. Method: We examined the presence of cannabinoid receptors (CB1 and CB2) and targets (TRPV1, TRPA1, Ca _V 3.1, Ca _V 3.2, Ca _V 3.3) via quantitative polymerase chain reaction (qPCR) in oral cancer cells SCC4, SCC9, SCC25, Cal27, and normal oral cell line OKF6. Result: Cannabinoid receptors are absent in all the cell lines, while TRPA1 is only present in normal cells, but absent in all the oral cancer cell lines. Voltage-gated calcium channels are present in all the cell lines. Conclusion and Future Aspects: TRPA1 could be the possible future prognostic indicator of oral squamous cell carcinoma. Future functionality assays could use precancerous cell lines to follow the loss of TRPA1.

The bacterial antigen, lipopolysaccharide (LPS) and disruptions in calcium channels are independently known to influence oral cancer progression. Previously, we found that bacterial antigens, LPS and lipoteichoic acid (LTA) act as confounders during the action of capsaicin on Cal 27 oral cancer proliferation. As calcium channel drugs may affect oral cancer cell proliferation, we investigated the effect of ML218 HCl, a T-type voltage-gated calcium channel blocker, on the proliferation of Cal 27 oral cancer cells. We hypothesized that ML218 HCl could effectively reduce LPS-induced oral cancer cell proliferation. LPS and LTA antigens were added to Cal 27 oral cancer cells either prior to and/or concurrently with ML218 HCl treatment, and the efficacy of the treatment was evaluated by measuring Cal 27 proliferation, cell death and apoptosis. ML218 HCl inhibited oral cancer cell proliferation, increased apoptosis and cell death, but their efficacy was significantly reduced in the presence of bacterial antigens. ML218 HCl proved more effective than capsaicin in reducing bacterial antigen-induced Cal 27 oral cancer cell proliferation. Our results also suggest an interplay of proliferation factors during the bacterial antigens and calcium channel drug interaction in Cal 27. Bacterial antigen reduction of drug efficacy should be considered for developing newer pharmacological agents or testing the efficacy of the existing oral cancer chemotherapeutic agents. Finally, voltage gated calcium channel drugs should be considered for future oral cancer research.