Publications by authors named "Else Driehuis"

13 Publications

  • Page 1 of 1

Author Correction: Establishment of patient-derived cancer organoids for drug-screening applications.

Nat Protoc 2021 Jan 12. Epub 2021 Jan 12.

Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center (UMC) Utrecht, Utrecht, the Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41596-021-00494-5DOI Listing
January 2021

Establishment of Pancreatic Organoids from Normal Tissue and Tumors.

STAR Protoc 2020 Dec 4;1(3):100192. Epub 2020 Dec 4.

Hubrecht Organoid Technology (HUB), Utrecht 3584 CM, the Netherlands.

Establishment of patient-derived adult stem cell-based pancreatic (tumor) organoids was first described in 2015. Since then, multiple laboratories have demonstrated the robustness of this method. We recently described the generation of a pancreatic cancer biobank containing 30 well-characterized tumor organoid models. Here, we describe the applied methods in detail. Use of tumor-selective media prevents contamination with normal cells. Generated organoids can be cryopreserved and can serve as a living biobank of pancreatic cancer for biomarker identification and drug screening. For complete information on the generation and use of this protocol, please refer to Driehuis et al. (2019).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xpro.2020.100192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757566PMC
December 2020

Establishment of patient-derived cancer organoids for drug-screening applications.

Nat Protoc 2020 10 14;15(10):3380-3409. Epub 2020 Sep 14.

Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center (UMC) Utrecht, Utrecht, the Netherlands.

Adult stem cell-based organoid technology is a versatile tool for the generation and long-term maintenance of near-native 3D epithelial tissues in vitro. The generation of cancer organoids from primary patient material enables a range of therapeutic agents to be tested in the resulting organoid cultures. Patient-derived cancer organoids therefore hold great promise for personalized medicine. Here, we provide an overview of the protocols used by different groups to establish organoids from various epithelial tissues and cancers, plus the different protocols subsequently used to test the in vitro therapy sensitivity of these patient-derived organoids. We also provide an in-depth protocol for the generation of head and neck squamous cell carcinoma organoids and their subsequent use in semi-automated therapy screens. Establishment of organoids and subsequent screening can be performed within 3 months, although this timeline is highly dependent on a.o. starting material and the number of therapies tested. The protocol provided may serve as a reference to successfully establish organoids from other cancer types and perform drug screenings thereof.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41596-020-0379-4DOI Listing
October 2020

Fasting-mimicking diet and hormone therapy induce breast cancer regression.

Nature 2020 07 15;583(7817):620-624. Epub 2020 Jul 15.

IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2502-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881940PMC
July 2020

Pancreatic cancer organoids recapitulate disease and allow personalized drug screening.

Proc Natl Acad Sci U S A 2019 Dec 9. Epub 2019 Dec 9.

Oncode Institute, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands;

We report the derivation of 30 patient-derived organoid lines (PDOs) from tumors arising in the pancreas and distal bile duct. PDOs recapitulate tumor histology and contain genetic alterations typical of pancreatic cancer. In vitro testing of a panel of 76 therapeutic agents revealed sensitivities currently not exploited in the clinic, and underscores the importance of personalized approaches for effective cancer treatment. The PRMT5 inhibitor EZP015556, shown to target (a gene commonly lost in pancreatic cancer)-negative tumors, was validated as such, but also appeared to constitute an effective therapy for a subset of MTAP-positive tumors. Taken together, the work presented here provides a platform to identify novel therapeutics to target pancreatic tumor cells using PDOs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1911273116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936689PMC
December 2019

Patient-Derived Head and Neck Cancer Organoids Recapitulate EGFR Expression Levels of Respective Tissues and Are Responsive to EGFR-Targeted Photodynamic Therapy.

J Clin Med 2019 Nov 5;8(11). Epub 2019 Nov 5.

Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands.

Patients diagnosed with head and neck squamous cell carcinoma (HNSCC) are currently treated with surgery and/or radio- and chemotherapy. Despite these therapeutic interventions, 40% of patients relapse, urging the need for more effective therapies. In photodynamic therapy (PDT), a light-activated photosensitizer produces reactive oxygen species that ultimately lead to cell death. Targeted PDT, using a photosensitizer conjugated to tumor-targeting molecules, has been explored as a more selective cancer therapy. Organoids are self-organizing three-dimensional structures that can be grown from both normal and tumor patient-material and have recently shown translational potential. Here, we explore the potential of a recently described HNSCC-organoid model to evaluate Epidermal Growth Factor Receptor (EGFR)-targeted PDT, through either antibody- or nanobody-photosensitizer conjugates. We find that EGFR expression levels differ between organoids derived from different donors, and recapitulate EGFR expression levels of patient material. EGFR expression levels were found to correlate with the response to EGFR-targeted PDT. Importantly, organoids grown from surrounding normal tissues showed lower EGFR expression levels than their tumor counterparts, and were not affected by the treatment. In general, nanobody-targeted PDT was more effective than antibody-targeted PDT. Taken together, patient-derived HNSCC organoids are a useful 3D model for testing in vitro targeted PDT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm8111880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912517PMC
November 2019

Oral Mucosal Organoids as a Potential Platform for Personalized Cancer Therapy.

Cancer Discov 2019 07 3;9(7):852-871. Epub 2019 May 3.

Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, the Netherlands.

Previous studies have described that tumor organoids can capture the diversity of defined human carcinoma types. Here, we describe conditions for long-term culture of human mucosal organoids. Using this protocol, a panel of 31 head and neck squamous cell carcinoma (HNSCC)-derived organoid lines was established. This panel recapitulates genetic and molecular characteristics previously described for HNSCC. Organoids retain their tumorigenic potential upon xenotransplantation. We observe differential responses to a panel of drugs including cisplatin, carboplatin, cetuximab, and radiotherapy . Additionally, drug screens reveal selective sensitivity to targeted drugs that are not normally used in the treatment of patients with HNSCC. These observations may inspire a personalized approach to the management of HNSCC and expand the repertoire of HNSCC drugs. SIGNIFICANCE: This work describes the culture of organoids derived from HNSCC and corresponding normal epithelium. These tumoroids recapitulate the disease genetically, histologically, and functionally. drug screening of tumoroids reveals responses to therapies both currently used in the treatment of HNSCC and those not (yet) used in clinical practice...
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-18-1522DOI Listing
July 2019

Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer.

Cancer Discov 2018 09 31;8(9):1112-1129. Epub 2018 May 31.

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.

Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection. New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-18-0349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125219PMC
September 2018

WNT signalling events near the cell membrane and their pharmacological targeting for the treatment of cancer.

Br J Pharmacol 2017 Dec 4;174(24):4547-4563. Epub 2017 Apr 4.

Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, The Netherlands.

WNT signalling is an essential signalling pathway for all multicellular animals. Although first described more than 30 years ago, new components and regulators of the pathway are still being discovered. Considering its importance in both embryonic development and adult homeostasis, it is not surprising that this pathway is often deregulated in human diseases such as cancer. Recently, it became clear that in addition to cytoplasmic components such as β-catenin, other, membrane-bound or extracellular, components of the WNT pathway are also altered in cancer. This review gives an overview of the recent discoveries on WNT signalling events near the cell membrane. Furthermore, membrane-associated components of the WNT pathway, which are more accessible for therapeutic intervention, as well therapeutic approaches that already target those components will be discussed. In this way, we hope to stimulate the development of effective anti-cancer therapies that target this fascinating pathway.

Linked Articles: This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.13758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727251PMC
December 2017

CRISPR/Cas 9 genome editing and its applications in organoids.

Am J Physiol Gastrointest Liver Physiol 2017 Mar 26;312(3):G257-G265. Epub 2017 Jan 26.

Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, The Netherlands;

Organoids are three-dimensional (3D) structures derived from adult or embryonic stem cells that maintain many structural and functional features of their respective organ. Recently, genome editing based on the bacterial defense mechanism CRISPR/Cas9 has emerged as an easily applicable and reliable laboratory tool. Combining organoids and CRISPR/Cas9 creates exciting new opportunities to study organ development and human disease in vitro. The potential applications of CRISPR in organoids are only beginning to be explored.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpgi.00410.2016DOI Listing
March 2017

CRISPR-Induced TMPRSS2-ERG Gene Fusions in Mouse Prostate Organoids.

JSM Biotechnol Biomed Eng 2017 28;4(1). Epub 2017 Mar 28.

Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), The Netherlands.

TMPRSS2-ERG fusions are common genetic events in prostate cancer. Until now, this genetic alteration was modelled by ERG overexpression. In this short communication, we report the creation of mouse prostate organoids that have undergone gene fusion through a CRISPR/Cas9-based strategy. The genetic fusion of TMPRSS2 and ERG results in ERG overexpression. This effect is androgen receptor-mediated, as expression of the fusion transcript can be restored to wildtype ERG levels by treatment with the androgen receptor antagonist Nilutamide.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287496PMC
March 2017

Organoid culture systems for prostate epithelial and cancer tissue.

Nat Protoc 2016 Feb 21;11(2):347-58. Epub 2016 Jan 21.

Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center (UMC) Utrecht, Utrecht, the Netherlands.

This protocol describes a strategy for the generation of 3D prostate organoid cultures from healthy mouse and human prostate cells (either bulk or FACS-sorted single luminal and basal cells), metastatic prostate cancer lesions and circulating tumor cells. Organoids derived from healthy material contain the differentiated luminal and basal cell types, whereas organoids derived from prostate cancer tissue mimic the histology of the tumor. We explain how to establish these cultures in the fully defined serum-free conditioned medium that is required to sustain organoid growth. Starting with the plating of digested tissue material, full-grown organoids can usually be obtained in ∼2 weeks. The culture protocol we describe here is currently the only one that allows the growth of both the luminal and basal prostatic epithelial lineages, as well as the growth of advanced prostate cancers. Organoids established using this protocol can be used to study many different aspects of prostate biology, including homeostasis, tumorigenesis and drug discovery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nprot.2016.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793718PMC
February 2016