An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity

Kopper, Oded; Witte, Chris J. de; Lõhmussaar, Kadi; Valle-Inclán, Jose Espejo; Hami, Nizar; Kester, Lennart; Balgobind, Anjali Vanita; Korving, Jeroen; Proost, Natalie; Begthel, Harry; Wijk, Lise M. van; Revilla, Sonia Aristín; Theeuwsen, Rebecca; Ven, Marieke van de; Roosmalen, Markus J. van; Ponsioen, Bas; Ho, Victor W.; Neel, Benjamin G.; Bosse, Tjalling; Gaarenstroom, Katja N.; Vrieling, Harry; Vreeswijk, Maaike P.G.; Diest, Paul J. van; Witteveen, Petronella O.; Jonges, Trudy N.; Bos, Johannes L.; Oudenaarden, Alexander van; Zweemer, Ronald P.; Snippert, Hugo J.G.; Kloosterman, Wigard P.; Clevers, Hans

doi:10.1038/s41591-019-0422-6

Cited by 604 publications

(757 citation statements)

References 74 publications

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“…Notably, we also clearly demonstrate that active BMP signaling is an important factor for the formation of cancer organoids (13/15 lines could only be initiated without Noggin in the medium), and for long-term growth. As Noggin was a standard medium component in previous studies (Hill et al, 2018;Kopper et al, 2019), this potentially explains the reported difficulties with long-term maintenance. Thus, it is tempting to speculate that the overall environment in the FT epithelium (with presumably high-Wnt signaling) represses cancer outgrowth and promotes escape of (pre-)malignant cells to more distant sites, like the surface of the ovaries and peritoneum.…”

Section: Discussionmentioning

confidence: 98%

“…As this patient-dependent effect of BMP2 addition was always neutral or positive, BMP2 was subsequently included in the standard medium composition. Therefore, the combination of EGF and BMP2, together with other standard components of organoid medium, i.e., ROCK inhibitor, TGF-b inhibitor, B27, N2, and nicotinamide (consistent with Kopper et al, 2019), was termed ovarian cancer minimal medium (OCM) ( Table EV3).…”

Section: Establishment Of Hgsoc Organoid Culturementioning

confidence: 99%

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Stable expansion of high‐grade serous ovarian cancer organoids requires a low‐Wnt environment

et al. 2020

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High‐grade serous ovarian cancer (HGSOC) likely originates from the fallopian tube (FT) epithelium. Here, we established 15 organoid lines from HGSOC primary tumor deposits that closely match the mutational profile and phenotype of the parental tumor. We found that Wnt pathway activation leads to growth arrest of these cancer organoids. Moreover, active BMP signaling is almost always required for the generation of HGSOC organoids, while healthy fallopian tube organoids depend on BMP suppression by Noggin. Fallopian tube organoids modified by stable shRNA knockdown of p53, PTEN, and retinoblastoma protein (RB) also require a low‐Wnt environment for long‐term growth, while fallopian tube organoid medium triggers growth arrest. Thus, early changes in the stem cell niche environment are needed to support outgrowth of these genetically altered cells. Indeed, comparative analysis of gene expression pattern and phenotypes of normal vs. loss‐of‐function organoids confirmed that depletion of tumor suppressors triggers changes in the regulation of stemness and differentiation.

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Section: Discussionmentioning

confidence: 98%

Section: Establishment Of Hgsoc Organoid Culturementioning

confidence: 99%

Stable expansion of high‐grade serous ovarian cancer organoids requires a low‐Wnt environment

et al. 2020

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“…(Toolan, ; Taetle et al , ; Fu et al , ; Beckhove et al , ; Fichtner et al , ; Shultz et al , ; Wang et al , ; Cutz et al , ; Sato et al , , ; Hennessey et al , ; Gao et al , ; Karthaus et al , ; Boj et al , ; Lee et al , ; Li et al , , ; Sachs et al , ; Yan et al , ; Kopper et al , ; Schutgens et al , ).…”

Section: Introductionunclassified

“…Moreover, organoid culture protocols have been established for patient‐derived tumour tissue as well. Human tumour organoids have been generated from colon (Sato et al , ; van de Wetering et al , ), pancreas (Boj et al , ; Huang et al , ), prostate (Gao et al , ; Drost et al , ), breast (Sachs et al , ), gastric (Nanki et al , ; Yan et al , ), lung (Sachs et al , ), oesophageal (Li et al , ), bladder (Lee et al , ; Mullenders et al , ), ovarian (Kopper et al , ), kidney (Schutgens et al , ) and liver (Broutier et al , ; Li et al , ) tumour tissue (Fig ). An important feature of a number of these PDTOs is that they genetically and phenotypically mirror the tumour epithelium, including its intra‐tumour heterogeneity (Huang et al , ; van de Wetering et al , ; Nanki et al , ; Sachs et al , ; Yan et al , ).…”

Section: Introductionmentioning

confidence: 99%

“…Timeline PDTX and PDTO development (Toolan, 1953;Taetle et al, 1987;Fu et al, 1992;Beckhove et al, 2003;Fichtner et al, 2004;Shultz et al, 2005;Wang et al, 2005;Cutz et al, 2006;Sato et al, 2009Sato et al, , 2011Hennessey et al, 2011;Gao et al, 2014;Karthaus et al, 2014;Boj et al, 2015;Lee et al, 2018;Li et al, 2018Li et al, , 2019Sachs et al, 2018;Yan et al, 2018;Kopper et al, 2019;Schutgens et al, 2019)…”

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Xenograft and organoid model systems in cancer research

et al. 2019

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Patient‐derived tumour xenografts and tumour organoids have become important preclinical model systems for cancer research. Both models maintain key features from their parental tumours, such as genetic and phenotypic heterogeneity, which allows them to be used for a wide spectrum of applications. In contrast to patient‐derived xenografts, organoids can be established and expanded with high efficiency from primary patient material. On the other hand, xenografts retain tumour–stroma interactions, which are known to contribute to tumorigenesis. In this review, we discuss recent advances in patient‐derived tumour xenograft and tumour organoid model systems and compare their promises and challenges as preclinical models in cancer research.

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The lncRNA ‘UCA1’ modulates the response to chemotherapy of ovarian cancer through direct binding to miR‐27a‐5p and control of UBE2N levels

et al. 2021

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Ovarian cancer (OC) is the leading cause of death in patients with gynecologic cancers. Due to late diagnosis and resistance to chemotherapy, the 5-year survival rate in patients with OC is below 40%. We observed that UCA1 a lncRNA previously reported to play an oncogenic role in several malignancies, is overexpressed in the chemoresistant OC cell line OAW42-R compared to their chemotherapy sensitive counterpart OAW42. Additionally, UCA1 overexpression was related to poor prognosis in two independent patient cohorts. Currently, the molecular mechanisms though which UCA1 acts in OC are poorly understood. We demonstrated that downregulation of the short isoform of UCA1 sensitized OC cells to cisplatin, and that UCA1 acted as competing endogenous RNA to miR-27a-5p. Upon UCA1 downregulation, miR-27a-5p downregulated its direct target UBE2N leading to the upregulation of BIM, a proapoptotic protein of the Bcl-2 family. The upregulation of BIM is the event responsible for the sensitization of OC cells to cisplatin. In order to model response to therapy in patients with OC, we used several patient-derived organoid cultures, a model faithfully mimicking patient's response to therapy.Inhibition of UBE2N sensitized patient-derived organoids to platinum salts. In conclusion, response to treatment in patients with OC is regulated by the UCA1/ miR-27a-5p/ UBE2N axis, where UBE2N inhibition could potentially represent a novel therapeutic strategy to counter chemoresistance in OC.

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An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity

Cited by 604 publications

References 74 publications

Stable expansion of high‐grade serous ovarian cancer organoids requires a low‐Wnt environment

Stable expansion of high‐grade serous ovarian cancer organoids requires a low‐Wnt environment

Xenograft and organoid model systems in cancer research

The lncRNA ‘UCA1’ modulates the response to chemotherapy of ovarian cancer through direct binding to miR‐27a‐5p and control of UBE2N levels

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