HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers

Shuling Ren; Daria A. Gaykalova; Theresa Guo; Alexander V. Favorov; Elana J. Fertig; Pablo Tamayo; Juan Luis Callejas-Valera; Mike Allevato; Mara Gilardi; Jessica Santos; Takahito Fukusumi; Akihiro Sakai; Mizuo Ando; Sayed Sadat; Chao Liu; Guorong Xu; Kathleen M. Fisch; Zhiyong Wang; Alfredo A. Molinolo; J. Silvio Gutkind; Trey Ideker; Wayne M. Koch; Joseph A. Califano

doi:10.1038/s41388-020-01431-8

HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers

Shuling Ren, Daria A. Gaykalova, Theresa Guo, Alexander V. Favorov, Elana J. Fertig, Pablo Tamayo, Juan Luis Callejas-Valera, Mike Allevato, Mara Gilardi, Jessica Santos, Takahito Fukusumi, Akihiro Sakai, Mizuo Ando, Sayed Sadat, Chao Liu, Guorong Xu, Kathleen M. Fisch, Zhiyong Wang, Alfredo A. Molinolo, J. Silvio GutkindTrey Ideker, Wayne M. Koch, Joseph A. Califano

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

36 Citations (Scopus)

Abstract

The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2/E4/E5, as well as association with lack of integration into the host genome. Models of the E2/E4/E5 carcinogenesis show p53 dependent enhanced proliferation in vitro, as well as increased susceptibility to induction of cancer in vivo. Whole genomic expression analysis of the E2/E4/E5 pharyngeal cancer subtype is defined by activation of the fibroblast growth factor receptor (FGFR) pathway and this subtype is susceptible to combination FGFR and mTOR inhibition, with implications for targeted therapy.

Original language	English
Pages (from-to)	6327-6339
Number of pages	13
Journal	Oncogene
Volume	39
Issue number	40
DOIs	https://doi.org/10.1038/s41388-020-01431-8
Publication status	Published - Oct 1 2020
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41388-020-01431-8

Cite this

Ren, S., Gaykalova, D. A., Guo, T., Favorov, A. V., Fertig, E. J., Tamayo, P., Callejas-Valera, J. L., Allevato, M., Gilardi, M., Santos, J., Fukusumi, T., Sakai, A., Ando, M., Sadat, S., Liu, C., Xu, G., Fisch, K. M., Wang, Z., Molinolo, A. A., ... Califano, J. A. (2020). HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers. Oncogene, 39(40), 6327-6339. https://doi.org/10.1038/s41388-020-01431-8

Ren, S, Gaykalova, DA, Guo, T, Favorov, AV, Fertig, EJ, Tamayo, P, Callejas-Valera, JL, Allevato, M, Gilardi, M, Santos, J, Fukusumi, T, Sakai, A, Ando, M, Sadat, S, Liu, C, Xu, G, Fisch, KM, Wang, Z, Molinolo, AA, Gutkind, JS, Ideker, T, Koch, WM & Califano, JA 2020, 'HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers', Oncogene, vol. 39, no. 40, pp. 6327-6339. https://doi.org/10.1038/s41388-020-01431-8

@article{1868cd9668aa4542a49d791de6d00606,

title = "HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers",

abstract = "The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2/E4/E5, as well as association with lack of integration into the host genome. Models of the E2/E4/E5 carcinogenesis show p53 dependent enhanced proliferation in vitro, as well as increased susceptibility to induction of cancer in vivo. Whole genomic expression analysis of the E2/E4/E5 pharyngeal cancer subtype is defined by activation of the fibroblast growth factor receptor (FGFR) pathway and this subtype is susceptible to combination FGFR and mTOR inhibition, with implications for targeted therapy.",

author = "Shuling Ren and Gaykalova, {Daria A.} and Theresa Guo and Favorov, {Alexander V.} and Fertig, {Elana J.} and Pablo Tamayo and Callejas-Valera, {Juan Luis} and Mike Allevato and Mara Gilardi and Jessica Santos and Takahito Fukusumi and Akihiro Sakai and Mizuo Ando and Sayed Sadat and Chao Liu and Guorong Xu and Fisch, {Kathleen M.} and Zhiyong Wang and Molinolo, {Alfredo A.} and Gutkind, {J. Silvio} and Trey Ideker and Koch, {Wayne M.} and Califano, {Joseph A.}",

note = "Funding Information: Acknowledgements We would like to thank Dennis Young, Joseph Aguilera for valuable advice and support. This work has been supported by National Institute of Dental and Craniofacial Research and NIH (R01 DE023347, JAC), the UC San Diego Clinical and Translational Research Institute Grant (UL1TR001442, KMF), NIH (P30 CA006973, AVF), Russian Basic Research Foundation (RBRF) (17-00-00208, AVF), and Russian Academy of Sciences Project (0112-2019-0001, AVF). Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2020",

month = oct,

day = "1",

doi = "10.1038/s41388-020-01431-8",

language = "English",

volume = "39",

pages = "6327--6339",

journal = "Oncogene",

issn = "0950-9232",

publisher = "Nature Publishing Group",

number = "40",

}

TY - JOUR

T1 - HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers

AU - Ren, Shuling

AU - Gaykalova, Daria A.

AU - Guo, Theresa

AU - Favorov, Alexander V.

AU - Fertig, Elana J.

AU - Tamayo, Pablo

AU - Callejas-Valera, Juan Luis

AU - Allevato, Mike

AU - Gilardi, Mara

AU - Santos, Jessica

AU - Fukusumi, Takahito

AU - Sakai, Akihiro

AU - Ando, Mizuo

AU - Sadat, Sayed

AU - Liu, Chao

AU - Xu, Guorong

AU - Fisch, Kathleen M.

AU - Wang, Zhiyong

AU - Molinolo, Alfredo A.

AU - Gutkind, J. Silvio

AU - Ideker, Trey

AU - Koch, Wayne M.

AU - Califano, Joseph A.

N1 - Funding Information: Acknowledgements We would like to thank Dennis Young, Joseph Aguilera for valuable advice and support. This work has been supported by National Institute of Dental and Craniofacial Research and NIH (R01 DE023347, JAC), the UC San Diego Clinical and Translational Research Institute Grant (UL1TR001442, KMF), NIH (P30 CA006973, AVF), Russian Basic Research Foundation (RBRF) (17-00-00208, AVF), and Russian Academy of Sciences Project (0112-2019-0001, AVF). Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2/E4/E5, as well as association with lack of integration into the host genome. Models of the E2/E4/E5 carcinogenesis show p53 dependent enhanced proliferation in vitro, as well as increased susceptibility to induction of cancer in vivo. Whole genomic expression analysis of the E2/E4/E5 pharyngeal cancer subtype is defined by activation of the fibroblast growth factor receptor (FGFR) pathway and this subtype is susceptible to combination FGFR and mTOR inhibition, with implications for targeted therapy.

AB - The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2/E4/E5, as well as association with lack of integration into the host genome. Models of the E2/E4/E5 carcinogenesis show p53 dependent enhanced proliferation in vitro, as well as increased susceptibility to induction of cancer in vivo. Whole genomic expression analysis of the E2/E4/E5 pharyngeal cancer subtype is defined by activation of the fibroblast growth factor receptor (FGFR) pathway and this subtype is susceptible to combination FGFR and mTOR inhibition, with implications for targeted therapy.

UR - http://www.scopus.com/inward/record.url?scp=85089869490&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85089869490&partnerID=8YFLogxK

U2 - 10.1038/s41388-020-01431-8

DO - 10.1038/s41388-020-01431-8

M3 - Article

C2 - 32848210

AN - SCOPUS:85089869490

SN - 0950-9232

VL - 39

SP - 6327

EP - 6339

JO - Oncogene

JF - Oncogene

IS - 40

ER -

HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this