Patient-derived organoids model cervical tissue dynamics and viral oncogenesis in cervical cancer
Lõhmussaar, Kadi; Oka, Rurika; Espejo Valle-Inclan, Jose; Smits, Milou H.H.; Wardak, Hila; Korving, Jeroen; Begthel, Harry; Proost, Natalie; van de Ven, Marieke; Kranenburg, Onno W.; Jonges, Trudy G.N.; Zweemer, Ronald P.; Veersema, Sebastiaan; van Boxtel, Ruben; Clevers, Hans
(2021) Cell stem cell, volume 28, issue 8, pp. 1380 - 1396.e6
(Article)
Abstract
Cervical cancer is a common gynecological malignancy often caused by high-risk human papillomavirus. There is a paucity of human-derived culture systems to study the cervical epithelium and the cancers derived thereof. Here we describe a long-term culturing protocol for ecto- and endocervical epithelia that generates 3D organoids that stably recapitulate
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the two tissues of origin. As evidenced for HSV-1, organoid-based cervical models may serve to study sexually transmitted infections. Starting from Pap brush material, a small biobank of tumoroids derived from affected individuals was established that retained the causative human papillomavirus (HPV) genomes. One of these uniquely carried the poorly characterized HPV30 subtype, implying a potential role in carcinogenesis. The tumoroids displayed differential responses to common chemotherapeutic agents and grew as xenografts in mice. This study describes an experimental platform for cervical (cancer) research and for future personalized medicine approaches.
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Keywords: cervical cancer, ectocervix, endocervix, HPV, HSV, organoids, Pap smear, Genetics, Molecular Medicine, Cell Biology, Journal Article
ISSN: 1934-5909
Publisher: Cell Press
Note: Funding Information: We thank A. Brousali, A. Snelting, K. Oosting, and C. Hulsbergen-Veelken of the Utrecht Platform for Organoid Technology (U-PORT) as well as C. de Witte and E. Stello for patient inclusion and tissue acquisition. We thank Anko de Graaff from the Hubrecht Imaging Centre (HIC) and the Utrecht Sequencing Facility (USEQ) for the library preparations, sequencing, and data analysis of cervical organoids. This work is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society and was funded by the gravitation program CancerGenomiCs.nl from the Netherlands Organisation for Scientific Research (NWO) and a grant from the Gieskes-Strijbis Foundation (1816199). R.v.B. was supported by a VIDI grant from the NWO (016.Vidi.171.023). Conceptualization, K.L. and H.C.; methodology, K.L. and H.C.; software, K.L. R.O. and J.E.V.-I.; formal analysis and data interpretation, K.L. R.O. J.E.V.-I. M.H.H.S. H.W. T.G.N.J. and R.v.B.; investigation, K.L. R.O. J.E.V.-I. M.H.H.S. and H.W.; technical support, J.K. and H.B.; transplantations, N.P. and M.v.d.V.; resources, O.W.K. R.P.Z. and S.V.; data curation, K.L. H.C. is an inventor on several patents involving adult stem cell-based organoid technology. His full declaration is given at https://www.uu.nl/staff/JCClevers/. Funding Information: We thank A. Brousali, A. Snelting, K. Oosting, and C. Hulsbergen-Veelken of the Utrecht Platform for Organoid Technology (U-PORT) as well as C. de Witte and E. Stello for patient inclusion and tissue acquisition. We thank Anko de Graaff from the Hubrecht Imaging Centre (HIC) and the Utrecht Sequencing Facility (USEQ) for the library preparations, sequencing, and data analysis of cervical organoids. This work is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society and was funded by the gravitation program CancerGenomiCs.nl from the Netherlands Organisation for Scientific Research (NWO) and a grant from the Gieskes-Strijbis Foundation ( 1816199 ). R.v.B. was supported by a VIDI grant from the NWO ( 016.Vidi.171.023 ). Publisher Copyright: © 2021 Elsevier Inc.
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