About our research group/lab
Our research
Our research focus includes:
- Modelling of prostate cancer: in vivo/ex vivo/in vitro
A unique set of 15 prostate cancer (PCa) patient-derived xenografts (PDX) has been established representing all stages of clinical PCa from early androgen responsive PCa towards late stage taxane-resistant disease. PDXs are maintained as subcutaneous xenografts in athymic nude mice. From two PDXs, we were able to generate permanent in vitro cell lines, PC346C and PC339C. Current efforts are directed to transfer our established PDXs into organoid lines. Meanwhile, we continue our efforts to generate novel organoid lines directly from the patient to keep up with clinical resistance towards contemporary treatments. Besides in vivo experimentation, we use ex vivo precision-cut tissue slices as an alternative screening tool.
- Metastasis
Metastatic PCa preferentially spreads to bone, lymph node, and liver. We have established a spontaneous metastasis model of PCa using our PC339C PDX. Fluorescently-tagged cells injected subcutaneously or orthotopically in athymic nude mice show metastatic shedding to all relevant mouse organs. reflecting metastatic disease seen in advanced PCa patients. These animals developed multiple macroscopic liver lesions with microscopic lesions in lymph nodes, lung and bone.
We are aiming to transfer this spontaneous metastasis PDX model into a fully humanized microfluidics organ-on-chip system using healthy human liver organoids.
Resistance mechanisms:
- Castration-resistance
Inactivation of the androgen receptor (AR) pathway by androgen deprivation therapy (ADT) is the mainstay of (metastatic) prostate cancer therapy. Ultimately, the AR pathway will be re-activated despite castrate levels of circulating androgens – thereby, maintaining its role even in castration resistant prostate cancer (CRPC). We have identified adrenal androgens as the main source for AR activation under ADT. Ref. Kumagai et al. 2013 doi: 10.1002/pros.22655.
We have generated multiple CRPC sublines with resistance to flutamide, bicalutamide, enzalutamide and abiraterone, which we use to identify novel drivers of resistance.
- Taxane-resistance
We investigate the impact of androgen receptor status on the efficacy of docetaxel and cabazitaxel using our PDXs models. We have shown cross-resistance between enzalutamide and docetaxel, underpinning the relevance of treatment sequence in the management of advanced disease. In vivo generated docetaxel resistant PDXs showed a role for drug transporters, such as the influx transporter SLCO1B3, to reach adequate tissue levels of docetaxel. Down-regulation of SLCO1B3 caused docetaxel resistance. Recently, we showed that cabazitaxel efficacy is highly effective in castrate setting with efficacy completely abolished in the presence of androgen. Ref van Soest et al. 2014 doi: 10.1016/j.eururo.2014.11.033; Mout et al. 2018 doi: 10.1016/j.ebiom.2017.12.024.
- Radio-resistance
Androgen-deprivation therapy has been shown to improve treatment outcome of external beam radiation therapy (EBRT) for locally advanced prostate cancer (PCa). DNA damage response (DDR) has been suggested to play a role in the underlying mechanism. We are studying the radiosensitizing effect of anti-androgens. Recently, we showed in tissue slices of PCa PDXs that androgen receptor suppression results in reduced non-homologous end-joining repair while DDR through HR was a secondary effect due to cell cycle change. Ref. Zhang et al. Cancers 2019 doi: 10.3390/cancers11101593.
- Theranostics: PSMA- and bombesin- radionuclide imaging and therapy
Appropriate staging is crucial for PCa as the presence of (even small) metastases outside the prostate strongly determines the prognosis and best choice of treatment. Currently, prostate specific membrane antigen (PSMA) radioligands are being used as imaging tool in the clinic. Besides, also the gastrin-releasing peptide receptor (bombesin) radioligands are being evaluated. The potential theranostic application of these imaging tracers for radionuclide therapy provides an interesting opportunity allowing for tumor-targeted radiation. The PDXs models are being used to evaluate novel radiotracers for imaging (using gamma-emitters e.g. 111In or positron-emitters e.g. 68Ga) and treatment (alpha-emitters e.g. 213Bi or beta-emitters e.g. 177Lu). Ref. Chatalic et al. 2016 doi: 10.7150/thno.14744.
Our projects
Human measurement models:
Development of humanized preclinical prostate cancer models, including organoids, for research and drug screening.
Advanced prostate cancer shows preferential spread towards bone, lymph node, and visceral organs, including liver and patients are treated with systemic therapy. Despite the fact that these therapies are used in the disseminated stage of disease, virtually all new drugs and therapies are being tested in preclinical “primary” tumour models. Preferential development of metastasis in specific organs indicates that invasion and colonisation of circulating tumour cells (CTCs) are strongly influenced by the organ host microenvironment which will likely also impact therapy response. Hence, it is highly relevant to apply early drug screens in models that reflect clinically relevant metastatic sites. To reach this objective, we propose to replace current models including animal systems, by a humanised 3D culture system that allows to study metastatic invasion of CTCs into different human healthy micro-tissues.
We established a spontaneous metastasis model of prostate cancer from patient-derived xenografts (PDXs). Fluorescently-labelled subcutaneous and orthotopic PDXs developed spontaneous (micro)-metastatic lesions in lymph node, lung, liver and bone of mice, mimicking the natural course of preferential metastatic disease in PCa patients. However, to overcome the limitations of the species differences in cell and organ characteristics of the mouse, we wish to establish a humanised 3D culture systems using the in vitro multi-tissue 3D organoid model applying the microfluidics system developed by InSphero, Schlieren, Switzerland.
To this end, we will co-culture healthy human liver tissue organoids with cancer cell suspensions to mimic CTCs. Using bright-field and fluorescent confocal microscopy we will follow tumour cell invasion and colonisation. The technological development and optimisation of the system will be complemented with proof-of-concept studies to test functionality and guide the optimisation process.
At the end of the project, we will deliver a bioassay for metastatic invasion of cancer cells into human liver and bone that can be applied in compound screens and drug testing. Transferability of the bioassay to other cancer types with metastatic phenotype, including bladder and breast cancer, will be piloted.
On the site of the Samenwerkende Gezondheidsfondsen you can find information (in Dutch) on the call which awarded this project a substantial grant.
Therapy resistance:
Elucidation of molecular mechanisms of docetaxel resistance and revealing cross-resistance of docetaxel and anti-androgen therapy in prostate cancer – collaborations with Sanofi and JNJ.
Targeted therapy and imaging: development of a novel PSMA-nanobody for PSMA-targeted imaging and radiotherapy of prostate cancer.
Immuno-oncology:
Immune interactions in novel syngenic prostate cancer model.
Key Publications
A complete overview of publications can be found here:
Wytske van Weerden
Key publications
Apalutamide Sensitizes Prostate Cancer to Ionizing Radiation via Inhibition of Non-Homologous End-Joining DNA Repair.
Zhang W, Liao CY, Chtatou H, Incrocci L, van Gent DC, van Weerden WM, Nonnekens J (2019) Cancers (Basel) 11; 2019: E1593.
A bypass mechanism of abiraterone-resistant prostate cancer: Accumulating CYP17A1 substrates activate androgen receptor signaling.
Moll JM, Kumagai J, van Royen ME, Teubel WJ, van Soest RJ, French PJ, Homma Y, Jenster G, de Wit R, van Weerden WM (2019) Prostate 2019;79:937-948.
Movember GAP1 PDX project: An international collection of serially transplantable prostate cancer patient-derived xenograft (PDX) models.
Navone NM, van Weerden WM, Vessella RL, Williams ED, Wang Y, Isaacs JT, Nguyen HM, Culig Z, van der Pluijm G, Rentsch CA, Marques RB, de Ridder CMA, Bubendorf L, Thalmann GN, Brennen WN, Santer FR, Moser PL, Shepherd P, Efstathiou E, Xue H, Lin D, Buijs J, Bosse T, Collins A, Maitland N, Buzza M, Kouspou M, Achtman A, Taylor RA, Risbridger G, Corey E (2018) Prostate. 2018 Dec;78(16):1262-1282.
Loss of SLCO1B3 drives taxane resistance in prostate cancer.
de Morrée ES, Böttcher R, van Soest RJ, Aghai A, de Ridder CM, Gibson AA, Mathijssen RH, Burger H, Wiemer EA, Sparreboom A, de Wit R, van Weerden WM(2016) Br J Cancer 2016;115:674-681.
Targeting the Androgen Receptor Confers In Vivo Cross-resistance Between Enzalutamide and Docetaxel, But Not Cabazitaxel, in Castration-resistant Prostate Cancer.
Van Soest RJ, de Morrée ES, Kweldam CF, de Ridder CM, Wiemer EA, Mathijssen RH, de Wit R, van Weerden WM (2015) Eur Urol 2015;67:981-985.
Thesis
- Rogier Schroeder (2011) The gastrin releasing peptide receptor as target for molecular imaging and therapy of prostate cancer using radiolabelled bombesin analogues.
- Hielke Meulenbelt (2012) Clinical & preclinical treatment aspects of castration resistant prostate cancer.
- Robert van Soest (2015) Taxanes and novel androgen receptor targeted agents in the management of metastatic castration-resistant prostate cancer.
- Kristel Chatalic (2016) Towards personalised treatment for prostate cancer: GRPR- and PSMA-targeted theranostic agents for imaging and therapy of prostate cancer.
- Ellen de Morree (2016) Finding biomarkers for taxane sensitivity in castration resistant prostate cancer.
Collaborations
Collaboration within Erasmus MC
Ongoing collaborative projects with:
Prof. M de Jong (Nuclear Medicine & Radiology). Targeted radionuclide imaging and therapy (‘theranostics’) for prostate cancer: PSMA, GRPR (bombesine receptor).
Prof. R de Wit, Dr. M Lolkema, Prof. J Martens (Medical Oncology). Taxane resistance and molecular analysis of circulating tumor cells in HSPC and CRPC.
Prof. L Incrocci (Radiotherapy) and Dr. J. Haeck (Radiology). Radio-resistance: hypoxia detection using MRI.
Dr. D van Gent, Dr. J Nonnekens (Mol Genetics). Radio-resistance and the DNA damage response.
Prof. J Debets (Med Oncology). Immuno-oncology of prostate cancer.
Dr. M van Royen (Pathology), Prof. L van de Laan (Surgery). Organoid-based organ-on-chip systems for liver metastasis.
Collaboration outside of Erasmus MC
Ongoing collaborative projects with:
Dr. G van de Pluijm (Urology, LUMC). PROPER - Near-patient’ prostate cancer models for the assessment of disease prognosis and therapy response.
Marie-Curie ITN Translational Research Network in Prostate Cancer TRANSPOT. Coordinator: H Leung, Glasgow University, www.crukscotlandinstitute.ac.uk
Movember Global Action Plan 1 on Patient-derived Xenograft (PDX) Models, www.movember.com
Consortium publication, onlinelibrary.wiley.com
Funding & Grants
- KWF 2015 Dr. G van de Pluijm (LUMC). PROPER Near-patient’ prostate cancer models for the assessment of disease prognosis and therapy response.
- KWF 2016 Prof. M de Jong (Nuclear Medicine/Radiology), Dr. WM van Weerden, Dr. D van Gent (Genetics). Hitting the prostate cancer cell via PSMA-targeted radiotherapy: safer and better.
- KWF 2016 Dr. M Lolkema, Prof. Martens (Med Oncology), Dr WM van Weerden. CIRCLE Towards liquid biopsies through leukapheresis: organoid culture of circulating tumor cells from blood of prostate cancer patients; is it feasible?
- Horizon 2020 Marie Sklodowska Curie Actions European Training Network Prof. Leung (Glasgow University). TRANSPOT Translational Research Network for Prostate Cancer.
- MRace 2017 Prof. J Debets, Dr. WM van Weerden. Immune interactions in novel syngenic prostate cancer model.
Various research collaborations are ongoing with industry for studying and testing new pharmaceuticals for prostate cancer in preclinical models.
