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

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

doi:10.1038/s41588-023-01357-3

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

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

^*Corresponding author for this work

Department of Molecular Cell Biology

Research output: Contribution to journal › Article › peer-review

21 Citations (Scopus)

Abstract

Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both HPV-positive and HPV-negative oropharyngeal tumors, uncovering a high level of cellular diversity within and between tumors. First, we detect diverse chromosomal aberrations within individual tumors, suggesting genomic instability and enabling the identification of malignant cells even at pathologically negative margins. Second, we uncover diversity with respect to HNSCC subtypes and other cellular states such as the cell cycle, senescence and epithelial-mesenchymal transitions. Third, we find heterogeneity in viral gene expression within HPV-positive tumors. HPV expression is lost or repressed in a subset of cells, which are associated with a decrease in HPV-associated cell cycle phenotypes, decreased response to treatment, increased invasion and poor prognosis. These findings suggest that HPV expression diversity must be considered during diagnosis and treatment of HPV-positive tumors, with important prognostic ramifications.

Original language	English
Pages (from-to)	640-650
Number of pages	11
Journal	Nature Genetics
Volume	55
Issue number	4
DOIs	https://doi.org/10.1038/s41588-023-01357-3
Publication status	Published - Apr 2023

Funding

Funding Information: This work was supported by the V Foundation (S.V.P.), Cancer Research Foundation (S.V.P.), Emerson Collective Cancer Research Fund (S.V.P.), Barnes Jewish Hospital Foundation (S.V.P.), NCI 1K08CA237732 (S.V.P), Doris Duke Fund to Retain Clinician Scientists (S.V.P.), Doris Duke Clinician Scientist Development Award (S.V.P.), NIDCD T32DC000022 (T.F.B.), the Swedish Society of Medicine (M.M.), Washington University Department of Medicine Faculty Diversity Award (J.S.F.), Israel Science Foundation (I.T.), Rising Tide Foundation (S.V.P. and I.T.), Mexican Friends New Generation Grant (I.T.), Mauricio Schwarz (I.T.), Zuckerman STEM Leadership Program (I.T.) and The Dr Celia Zwillenberg-Fridman and Dr Lutz Zwillenberg Career Development Chair (I.T.). The funding sources had no involvement in the design, conduct and reporting of the research. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

All Science Journal Classification (ASJC) codes

Genetics

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10.1038/s41588-023-01357-3

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Puram, S. V., Mints, M., Pal, A., Qi, Z., Reeb, A., Gelev, K., Barrett, T. F., Gerndt, S., Liu, P., Parikh, A. S., Ramadan, S., Law, T., Mroz, E. A., Rocco, J. W., Adkins, D., Thorstad, W. L., Gay, H. A., Ding, L., Paniello, R. C., ... Tirosh, I. (2023). Cellular states are coupled to genomic and viral heterogeneity in HPV-related oropharyngeal carcinoma. Nature Genetics, 55(4), 640-650. https://doi.org/10.1038/s41588-023-01357-3

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title = "Cellular states are coupled to genomic and viral heterogeneity in HPV-related oropharyngeal carcinoma",

abstract = "Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both HPV-positive and HPV-negative oropharyngeal tumors, uncovering a high level of cellular diversity within and between tumors. First, we detect diverse chromosomal aberrations within individual tumors, suggesting genomic instability and enabling the identification of malignant cells even at pathologically negative margins. Second, we uncover diversity with respect to HNSCC subtypes and other cellular states such as the cell cycle, senescence and epithelial-mesenchymal transitions. Third, we find heterogeneity in viral gene expression within HPV-positive tumors. HPV expression is lost or repressed in a subset of cells, which are associated with a decrease in HPV-associated cell cycle phenotypes, decreased response to treatment, increased invasion and poor prognosis. These findings suggest that HPV expression diversity must be considered during diagnosis and treatment of HPV-positive tumors, with important prognostic ramifications.",

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

year = "2023",

month = apr,

doi = "10.1038/s41588-023-01357-3",

language = "English",

volume = "55",

pages = "640--650",

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Puram, SV, Mints, M, Pal, A, Qi, Z, Reeb, A, Gelev, K, Barrett, TF, Gerndt, S, Liu, P, Parikh, AS, Ramadan, S, Law, T, Mroz, EA, Rocco, JW, Adkins, D, Thorstad, WL, Gay, HA, Ding, L, Paniello, RC, Pipkorn, P, Jackson, RS, Wang, X, Mazul, A, Chernock, R, Zevallos, JP, Silva-Fisher, J & Tirosh, I 2023, 'Cellular states are coupled to genomic and viral heterogeneity in HPV-related oropharyngeal carcinoma', Nature Genetics, vol. 55, no. 4, pp. 640-650. https://doi.org/10.1038/s41588-023-01357-3

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AU - Puram, Sidharth V.

AU - Mints, Michael

AU - Pal, Ananya

AU - Qi, Zongtai

AU - Reeb, Ashley

AU - Gelev, Kyla

AU - Barrett, Thomas F.

AU - Gerndt, Sophie

AU - Liu, Ping

AU - Parikh, Anuraag S.

AU - Ramadan, Salma

AU - Law, Travis

AU - Mroz, Edmund A.

AU - Rocco, James W.

AU - Adkins, Doug

AU - Thorstad, Wade L.

AU - Gay, Hiram A.

AU - Ding, Li

AU - Paniello, Randal C.

AU - Pipkorn, Patrik

AU - Jackson, Ryan S.

AU - Wang, Xiaowei

AU - Mazul, Angela

AU - Chernock, Rebecca

AU - Zevallos, Jose P.

AU - Silva-Fisher, Jessica

AU - Tirosh, Itay

PY - 2023/4

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N2 - Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both HPV-positive and HPV-negative oropharyngeal tumors, uncovering a high level of cellular diversity within and between tumors. First, we detect diverse chromosomal aberrations within individual tumors, suggesting genomic instability and enabling the identification of malignant cells even at pathologically negative margins. Second, we uncover diversity with respect to HNSCC subtypes and other cellular states such as the cell cycle, senescence and epithelial-mesenchymal transitions. Third, we find heterogeneity in viral gene expression within HPV-positive tumors. HPV expression is lost or repressed in a subset of cells, which are associated with a decrease in HPV-associated cell cycle phenotypes, decreased response to treatment, increased invasion and poor prognosis. These findings suggest that HPV expression diversity must be considered during diagnosis and treatment of HPV-positive tumors, with important prognostic ramifications.

AB - Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both HPV-positive and HPV-negative oropharyngeal tumors, uncovering a high level of cellular diversity within and between tumors. First, we detect diverse chromosomal aberrations within individual tumors, suggesting genomic instability and enabling the identification of malignant cells even at pathologically negative margins. Second, we uncover diversity with respect to HNSCC subtypes and other cellular states such as the cell cycle, senescence and epithelial-mesenchymal transitions. Third, we find heterogeneity in viral gene expression within HPV-positive tumors. HPV expression is lost or repressed in a subset of cells, which are associated with a decrease in HPV-associated cell cycle phenotypes, decreased response to treatment, increased invasion and poor prognosis. These findings suggest that HPV expression diversity must be considered during diagnosis and treatment of HPV-positive tumors, with important prognostic ramifications.

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

Abstract

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