Fibroblasts in Head and Neck Squamous Cell Carcinoma Associated With Perineural Invasion Have High-Level Nuclear Yes-Associated Protein (YAP) Expression

Wang, Yanghua; Gersten, Adam; Moleirinho, Susana; Gunn-Moore, Frank J.; Reynolds, Paul A.; Prystowsky, Michael B.

doi:10.1177/2374289515616972

Cited by 6 publications

(5 citation statements)

References 16 publications

(22 reference statements)

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“…4 . Accordingly, levels of nuclear YAP/TAZ in fibroblasts associated with perineural invasion of HNSCC were higher than those in the stroma of normal mucosa 175 . YAP expression was elevated at the invasive front of HNSCC tumours 176 and also as a consequence of PIK3CA overexpression 177 .…”

Section: Ferroptosismentioning

confidence: 86%

Cell death in head and neck cancer pathogenesis and treatment

Raudenská

Masařík

2021

Cell Death Dis

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Many cancer therapies aim to trigger apoptosis in cancer cells. Nevertheless, the presence of oncogenic alterations in these cells and distorted composition of tumour microenvironment largely limit the clinical efficacy of this type of therapy. Luckily, scientific consensus describes about 10 different cell death subroutines with different regulatory pathways and cancer cells are probably not able to avoid all of cell death types at once. Therefore, a focused and individualised therapy is needed to address the specific advantages and disadvantages of individual tumours. Although much is known about apoptosis, therapeutic opportunities of other cell death pathways are often neglected. Molecular heterogeneity of head and neck squamous cell carcinomas (HNSCC) causing unpredictability of the clinical response represents a grave challenge for oncologists and seems to be a critical component of treatment response. The large proportion of this clinical heterogeneity probably lies in alterations of cell death pathways. How exactly cells die is very important because the predominant type of cell death can have multiple impacts on the therapeutic response as cell death itself acts as a second messenger. In this review, we discuss the different types of programmed cell death (PCD), their connection with HNSCC pathogenesis and possible therapeutic windows that result from specific sensitivity to some form of PCD in some clinically relevant subgroups of HNSCC.

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Section: Ferroptosismentioning

confidence: 86%

Cell death in head and neck cancer pathogenesis and treatment

Raudenská

Masařík

2021

Cell Death Dis

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“…To perform a preliminary analysis of the role of non-malignant cells in PNI, we evaluated the expression levels of the genes in the key coexpression module, especially the hub genes. We found that these genes were mainly enriched in fibroblasts, an important component of the tumor stroma that contributes to the shaping of the ECM, the metabolic and immune reprogramming of the TME, and the release of growth factors that promote tumor growth and invasion (39, 40). Interestingly, cancer-associated fibroblasts (CAFs) have been found to be in close proximity to p-EMT cells in the surrounding TME.…”

Section: Discussionmentioning

confidence: 99%

Integrating Clinical and Genetic Analysis of Perineural Invasion in Head and Neck Squamous Cell Carcinoma

et al. 2019

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Introduction: Perineural invasion (PNI), a key pathological feature of head and neck squamous cell carcinoma (HNSCC), predicts poor survival. However, the associated clinical characteristics remain uncertain, and the molecular mechanisms are largely unknown. Materials and methods: HNSCC gene expression and corresponding clinical data were downloaded from The Cancer Genome Atlas (TCGA). Prognostic subgroup analysis was performed, and potential PNI risk factors were assessed with logistic regression. PNI-associated gene coexpression modules were identified with weighted gene coexpression network analysis (WGCNA), and key module gene functions and the roles of non-malignant cells in PNI were evaluated with a single-cell transcriptomic dataset (GSE103322). Results: PNI was significantly inversely associated with overall survival (HR, 2.08; 95% CI, 1.27 to 3.40; P = 0.004), especially in advanced patients (HR, 2.62; 95% CI, 1.48 to 4.64; P < 0.001). Age, gender, smoking history, and alcohol history were not risk factors. HPV-positive cases were less likely than HPV-negative cases to develop PNI (OR, 0.28; 95% CI, 0.09 to 0.76; P = 0.017). WGCNA identified a unique significantly PNI-associated coexpression module containing 357 genes, with 12 hub genes (TIMP2, MIR198, LAMA4, FAM198B, MIR4649, COL5A1, COL1A2, OLFML2B, MMP2, FBN1, ADAM12, and PDGFRB). Single-cell transcriptomic data analysis revealed that the genes in the PNI-associated module correlated with the signatures “EMT,” “metastasis,” and “invasion.” Among non-malignant cells, fibroblasts had relatively high expression of the key genes. Conclusion: At the molecular and omic levels, we verified that PNI in HNSCC is a process of invasion rather than simple diffusion. Fibroblasts probably play an important role in PNI. Novelty & Impact Statements The study is a thorough analysis of PNI in HNSCC from the clinical level to the molecular level and presents the first description of cancer-related PNI from the omics perspective to date as far as we know. We verified that PNI in HNSCC is a process of invasion rather than simple diffusion, at the molecular and omic levels. Fibroblasts were found to probably play an important role in PNI by analyzing single-cell transcriptomic data.

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“…Our finding of increased cytoplasmic pYAP is similar to previous studies conducted by Cao et al [ 25 ] and Yeo et al [ 24 ], which found higher cytoplasmic pYAP expression in an early or lower histological grade of breast cancer and esophageal squamous cell carcinoma (ESCC), respectively. Additionally, increased cytoplasmic pYAP expression was also found in the cancer-associated fibroblast (CAFs) and tumor cells of head and neck squamous cell carcinoma [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Rigid Tissue Increases Cytoplasmic pYAP Expression in Pre-Malignant Stage of Lung Squamous Cell Carcinoma (SCC) In Vivo

Zakaria

Kiew

Rajab

et al. 2022

CIMB

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Increased tissue rigidity is able to activate the Hippo signaling pathway, leading to YAP inactivation by phosphorylation and translocation into the cytoplasm. Accumulating evidence suggests that cytoplasmic pYAP serves as a tumor suppressor and could be a prognostic biomarker for several solid cancers. However, the relationship between tissue rigidity and cytoplasmic pYAP expression in the early stage of lung squamous cell carcinoma (SCC) remains elusive; this was determined in this study by using a mouse model. Female BALB/c mice were assigned into two groups (n = 6; the vehicle (VC) and the pre-malignant (PM) group, which received 70% acetone and 0.04 M N-nitroso-tris-chloroethylurea (NTCU) for 15 weeks, respectively. In this study, the formation of hyperplasia and metaplasia lesions was found in the PM group, indicating the pre-malignant stage of lung SCC. The pre-malignant tissue appeared to be more rigid as characterized by significantly higher (p < 0.05) epithelium thickness, proliferative activity, and collagen content than the VC group. The PM group also had a significantly higher (p < 0.05) cytoplasmic pYAP protein expression than the VC group. In conclusion, increased tissue rigidity may contribute to the upregulation of cytoplasmic pYAP expression, which may act as a tumor suppressor in the early stage of lung SCC.

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Fibroblasts in Head and Neck Squamous Cell Carcinoma Associated With Perineural Invasion Have High-Level Nuclear Yes-Associated Protein (YAP) Expression

Cited by 6 publications

References 16 publications

Cell death in head and neck cancer pathogenesis and treatment

Cell death in head and neck cancer pathogenesis and treatment

Integrating Clinical and Genetic Analysis of Perineural Invasion in Head and Neck Squamous Cell Carcinoma

Rigid Tissue Increases Cytoplasmic pYAP Expression in Pre-Malignant Stage of Lung Squamous Cell Carcinoma (SCC) In Vivo

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