Cellular states are coupled to genomic and viral heterogeneity in HPV-related oropharyngeal carcinoma

Puram, Sidharth V.; Mints, Michael; Pal, Ananya; Qi, Zongtai; Reeb, Ashley N.; Gelev, Kyla; Barrett, Thomas F.; Gerndt, Sophie P.; Liu, Ping; Parikh, Anuraag S.; Ramadan, Salma; Law, Travis; Mroz, Edmund A.; Rocco, James W.; Adkins, Doug; Thorstad, Wade L.; Gay, Hiram A.; Li, Ding; Paniello, Randal C.; Pipkorn, Patrik; Jackson, Ryan; Wang, Xiaowei; Mazul, Angela L.; Chernock, Rebecca D.; Zevallos, José P.; Silva-Fisher, Jessica; Tirosh, Itay

doi:10.1038/s41588-023-01357-3

Cited by 34 publications

(19 citation statements)

References 46 publications

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“…OSCC onset often relates to chronic exposure to genotoxic compounds, which in turn leads to genetic instability and the dysregulation of the DNA repair process 7 . Clones with acquired genetic alterations have an initial growth advantage and can potentially transform into aggressive subclones in the more advanced stages of the disease 11,12,13 . High-risk premalignant lesions can be subtle, and timely recognition relies on the detection of stage-specific molecular biomarkers.…”

Section: Mainmentioning

confidence: 99%

The Notch1/Delta-like-4 axis is crucial for the initiation and progression of oral squamous cell carcinoma

Meisel,

Destefani,

Valookkaran

et al. 2024

Preprint

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The Notch signaling pathway is frequently altered in oral squamous cell carcinoma (OSCC), the most common malignant neoplasm of the oral mucosa. This study aimed to elucidate the functional role of this pathway in both the initiation and progression of OSCC. Using transgenic animal models, advanced imaging, and next-generation-sequencing techniques, we analyzed Notch-dependent changes driving OSCC. We found specific expression patterns of Notch1 and Delta-like-4 confined to the malignant tissue, while Jagged1 was downregulated in OSCC. This mutually exclusive expression of Delta-like-4 and Jagged1 occurs at the early hyperplastic stage and persists until more advanced stages of the developing tumor. Transcriptomic analyses confirmed the dysregulation of the Notch pathway circuitry and of the genes associated with the undifferentiated state of OSCC cells. Furthermore, pharmacological Notch inhibition significantly impaired cancer cell motility. Taken together, these results reveal the pivotal importance of the Notch1/Delta-like-4 signaling axis as a central oncogenic driver in OSCC.

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Section: Mainmentioning

confidence: 99%

The Notch1/Delta-like-4 axis is crucial for the initiation and progression of oral squamous cell carcinoma

Meisel,

Destefani,

Valookkaran

et al. 2024

Preprint

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“…Yet, it should be emphasized that the sample size in these studies is limited; therefore, future research with larger cohorts is needed to further validate the reliability of these biomarkers. Moreover, the advancements and application of single‐cell sequencing and deep learning networks have provided additional potential biomarkers for the diagnosis and prognosis of HPV‐related tumors 17–19 …”

Section: Hpv Biologymentioning

confidence: 99%

Advances in HPV‐associated tumor management: Therapeutic strategies and emerging insights

Gong

Chi

Xia

et al. 2023

Journal of Medical Virology

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With the rapid increase in the incidence of cervical cancer, anal cancer and other cancers, human papillomavirus (HPV) infection has become a growing concern.Persistent infection with high-risk HPV is a major cause of malignant tumors. In addition, microbiota and viruses such as human immunodeficiency virus, herpes simplex virus, and Epstein-Barr virus are closely associated with HPV infection. The limited effectiveness of existing treatments for HPV-associated tumors and the high rates of recurrence and metastasis in patients create an urgent need for novel and effective approaches. In recent years, HPV vaccine coverage has increased and can reduce the incidence of serious adverse events. Overall, this article provides a comprehensive overview of HPV biology, microbiome, and other viral interactions in cancer development, highlighting the need for a more comprehensive approach to cancer prevention and treatment. Current and emerging HPV-related cancer control and treatment strategies are also further explored.

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“…While HPV + OPSCC subtypes mentioned above reflect heterogeneity at inter-patient level, single-cell sequencing studies also revealed huge intratumoral heterogeneity within the same patient [ 95 , 96 ]. Intratumoral heterogeneity is the phenomenon where different cell populations coexist in the same tumor; metastasis and treatment resistance may result when aggressive or persistor clones are selected over others.…”

Section: Molecular Heterogeneity Of Hpv+opsccmentioning

confidence: 99%

“…Intratumoral heterogeneity is the phenomenon where different cell populations coexist in the same tumor; metastasis and treatment resistance may result when aggressive or persistor clones are selected over others. In HPV + OPSCC cancer cells, variations in chromosomal aberrations, pathway activation, and HPV viral gene transcript expression were reported between and within tumors with important prognostic implications [ 95 ]. Moreover, HPV + OPSCC also showed differing intratumoral inflammation and fibroblast elastic differentiation plasticity [ 96 ].…”

Section: Molecular Heterogeneity Of Hpv+opsccmentioning

confidence: 99%

Clinical, morphologic and molecular heterogeneity of HPV-associated oropharyngeal cancer

Lim,

Mierzwa,

Sartor

et al. 2023

Oncogene

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The incidence of human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is rising rapidly and has exceeded cervical cancer to become the most common HPV-induced cancer in developed countries. Since patients with HPV + OPSCC respond very favorably to standard aggressive treatment, the emphasis has changed to reducing treatment intensity. However, recent multi-center clinical trials failed to show non-inferiority of de-escalation strategies on a population basis, highlighting the need to select low-risk patients likely to respond to de-intensified treatments. In contrast, there is a substantial proportion of patients who develop recurrent disease despite aggressive therapy. This supports that HPV + OPSCC is not a homogeneous disease, but comprises distinct subtypes with clinical and biological variations. The overall goal for this review is to identify biomarkers for HPV + OPSCC that may be relevant for patient stratification for personalized treatment. We discuss HPV + OPSCC as a heterogeneous disease from multifaceted perspectives including clinical behavior, tumor morphology, and molecular phenotype. Molecular profiling from bulk tumors as well as single-cell sequencing data are discussed as potential driving factors of heterogeneity between tumor subgroups. Finally, we evaluate key challenges that may impede in-depth investigations of HPV + OPSCC heterogeneity and outline potential future directions, including a section on racial and ethnic differences.

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Cellular states are coupled to genomic and viral heterogeneity in HPV-related oropharyngeal carcinoma

Cited by 34 publications

References 46 publications

The Notch1/Delta-like-4 axis is crucial for the initiation and progression of oral squamous cell carcinoma

The Notch1/Delta-like-4 axis is crucial for the initiation and progression of oral squamous cell carcinoma

Advances in HPV‐associated tumor management: Therapeutic strategies and emerging insights

Clinical, morphologic and molecular heterogeneity of HPV-associated oropharyngeal cancer

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