Jos Jonkers
Amsterdam
Breast cancer researcher, group leader at Oncode Institute and the Netherlands Cancer Institute
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Articles by Jos Jonkers
PUM3 is an essential suppressor of replication stress in homologous recombination deficient breast cancer
Abstract Most Triple Negative Breast Cancers (TNBCs) are p53 mutant high-grade invasive ductal carcinomas with a basal-like transcriptional programme. A large proportion of TNBCs also have mutation signatures indicating defective homologous recombination (HR) DNA repair. While HR deficiency is mutagenic and oncogenic, it can also compromise cell fitness.
The anion channel GPR89 is a tumor-specific dependency in breast cancer
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Abstract How cancers regulate endoplasmic reticulum (ER) pH and minimize ER stress remains unclear. Here we show that in breast cancer, these processes are governed by the anion channel GPR89. While normally localized to the Golgi, we find GPR89 is also present in the ER of tumor cells, where it collaborates with vacuolar H⁺ ATPase to regulate pH, and reduces ER stress via IRE1α-HSP47-XBP1s, ATF6 and ATP2A2 pathways.
By Riccardo Ferro, Alexandra Nicewicz Carroll, Virinder Reen, George Vlachogiannis, Rebeca Uceda-Castro, Dragomir B. Krastev, Valeria Amodeo, Stephen Pettitt, Nadja D’Uonno, Ioanna Mavrommati, Blanca Navarro, Luke Hitchen, Jennifer Trendell, Ana Stojiljkovic, Cynthia Prince, Ioannis Roxanis, Patrycja Gazinska, Daniel Larcombe-Young, Rebecca Marlow, Stefano Annunziato, Jos Jonkers, Nalan Liv, John Alexander, Jelmar S. Quist, Mercedes Pardo, Theodoros I. Roumeliotis, Jyoti Choudhary, Daniel Weekes, Joanna I Loizou, Rachael Natrajan, Anita Grigoriadis, Syed Imran Haider, Christopher Lord Verified, Andrew Tutt, Ana M. Mendes-Pereira, Narinder Janghra, Tejashree Rajaram Kanitkar, Amadeus Xu, Nirmesh Patel, Pierfrancesco Marra, Mallur Srivatsan Madhusudhan
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Nature
Verified
E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular breast cancer
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Abstract Invasive lobular breast carcinoma (ILC) shows specific stromal features, and a high tumor-infiltrating lymphocyte (TIL) content being associated with poor patient prognosis. Here, we reveal the underlying mechanism by performing single-cell analysis, immunohistochemistry, deconvolution of bulk RNA-sequencing in a large female ILC series and functional assays.
By Lounes Djerroudi, Rana Mhaidly, Yann Kieffer, Isabelle Damei, Géraldine Gentric, Laetitia Fuhrmann, Andreia VAS Goncalves, Andreia Salgado Gonçalves, Renaud Leclere, Enora Laas, Caroline Malhaire, Kim Cao, Julia M. Houthuijzen, Jos Jonkers, Camille Benoist, Victor Renault, François-Clément Bidard, Anne Vincent-Salomon, Fatima Mechta-Grigoriou, Hugo Croizer, Vithuzane Selvarasa, Martial Caly, Camille Richardot, Pim Kloosterman
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Nature
Verified
Enabling DCIS subtyping: leveraging foundation models for robust grading and molecular biomarker scoring
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Abstract Ductal Carcinoma In Situ (DCIS) is a non-obligate precursor of invasive breast cancer. Due to a lack of reliable prognostic markers, nearly all women with DCIS undergo intensive treatment—often unnecessarily. The LORD trial addresses this by offering active surveillance to women with screen-detected, ER-positive, HER2-negative, grade 1 or 2 DCIS, aiming to reduce overtreatment.
By S. R. Doyle, J. Brunekreef, E. A. Marcus, Y. Liu, E. Sawyer, A. M. Thompson, S. E. Pinder, Jelle Wesseling, Alastair Thompson, Serena Nik-Zainal, Elinor Sawyer, Helen Davies, Andrew Futreal, Nicholas E Navin, E. Shelley Hwang, Jos Jonkers, Jacco van Rheenen, Fariba Behbod, Esther H. Lips, Marjanka K. Schmidt, Lodewyk Wessels, Daniel Rea, Proteeti Bhattacharjee, Hilary Stobart, Deborah E. Collyar, Donna Pinto, Ellen Verschuur, Marja van Oirsouw, J. Wesseling, E. H. Lips, M. A. Oerlemans, L. Mulder, I. Bouybayoune, C. I. Sánchez, J. Teuwen
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Nature
Verified
High-throughput spheroid-based assay for functional breast cancer precision medicine facilitated by deep learning - Communications Medicine
Abstract Despite rapid advances in treatment, breast cancer remains the leading cause of cancer mortality in women, with triple negative breast cancers having a particularly poor prognosis. Some tumors have (epi)genetic alterations causing homologous recombination deficiency, providing opportunities for targeted therapeutics including poly (ADP-ribose) polymerase inhibitors.
Insights from three decades of BRCA1/2 modeling in mice - Nature Genetics
Abstract Since the discovery of the BRCA1 and BRCA2 (hereafter referred to as BRCA1/2) hereditary breast and ovarian cancer genes three decades ago, genetically engineered and patient-derived mouse models have been instrumental in advancing our understanding of BRCA1/2 biology, particularly their roles in normal development, tumor suppression and therapy response.
MDC1 counteracts replication fork reversal and mediates chemosensitivity in BRCA1/2-deficient tumors - Oncogene
Abstract MDC1 is a key protein in DNA damage signaling. When DNA double-strand breaks (DSBs) occur, MDC1 localizes to the sites of DNA damage to promote the recruitment of other factors, including the 53BP1-mediated DSB repair pathway. By studying mechanisms of poly (ADP-ribose) polymerase inhibitor (PARPi) resistance in BRCA2; p53-deficient mouse mammary tumors, we identified a thus far unknown role of MDC1 in replication fork biology.
Fasting boosts breast cancer therapy efficacy via glucocorticoid activation - Nature
Abstract The majority of breast cancers are driven by oestrogen receptor-α (ERα) activation, and endocrine therapy represents the mainstay treatment for these patients1. However, resistance is common and tumours often progress after years of endocrine suppression2. Periodic fasting enhances the efficacy of standard endocrine therapy and delays acquired drug resistance, although the underlying mechanisms remain unclear3.
NAA60 facilitates LRRC8A- and LRRC8D-mediated platinum drug uptake - Communications Biology
Abstract The platinum-based drugs cis- and carboplatin, which are crucial for treating cancers with DNA repair defects, like those caused by BRCA1/2 mutations, rely on the volume-regulated anion channel subunits LRRC8A and LRRC8D for about 50% of cellular drug uptake. Yet, the precise mechanisms of how LRRC8A and LRRC8D mediate this function are largely unknown. Here, we identify NAA60, an N-terminal acetyltransferase, which localizes to the Golgi apparatus to affect LRRC8A and LRRC8D function.
The pan-cancer proteome atlas, a mass spectrometry-based landscape for discovering tumor biology, biomarkers, and therapeutic targets
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1Amsterdam UMC, location Vrije Universiteit Amsterdam, Department of Medical Oncology, OncoProteomics Laboratory, De Boelelaan 1117, Amsterdam, the Netherlands 2Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, the Netherlands 3School of Medicine, Westlake University, Hangzhou, Zhejiang, China 4Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China 5Amsterdam UMC location Vrije Universiteit Amsterdam, Department of...
By Jaco C. Knol, Mengge Lyu, Franziska Böttger, Madalena Nunes Monteiro, Thang V. Pham, Frank Rolfs, Andrea Vallés-Martí, Tim Schelfhorst, Irene V. Bijnsdorp, Shuaiyao Wang, Fangfei Zhang, Bart Westerman, Barbara Sitek, Janne Lehtiö, Jan Koster, Jan IJzermans, Maarten F. Bijlsma, Jan Paul Medema, Alex A. Henneman, Sander R. Piersma, Ruud H Brakenhoff, Jacqueline Cloos, Valentina Cordo', Daphne de Jong, Geert Kazemier, Danijela Koppers-Lalic, Mariette Labots, John Martens, Jules P.P. Meijerink, Madiha Mumtaz, Chantal Scheepbouwer, Robby E. Kibbelaar, David P. Noske, Renske D.M. Steenbergen, Winan van Houdt, Elisa Giovannetti, Jos Jonkers, tong liu, Meisi Yan, Xiaolu Zhan, Tiannan Guo, Connie R. Jimenez
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Cell Press
Verified
SRBD1, a highly conserved gene required for chromosome individualization
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Keywords SRBD1 condensin topoisomerase II chromosome individualization decatenation Research topic(s) CP: Molecular biology Introduction Cell viability is dependent on several key processes, such as translation, mRNA processing, intracellular transport, and cell division. Consequently, key factors that are required for the function of tRNAs, ribosomes, and chaperones are commonly essential for cell viability (DepMap portal1).
By Jonne Raaijmakers, Louise M.E. Janssen, Abdelghani Mazouzi, Amber L.H. Hondema, Razvan Borza, Alexander Fish, Ahmed M.O. Elbatsh, Justina Kazokaitė-Adomaitienė, Nuria Vaquero-Siguero, Isabel Mayayo-Peralta, Leila Nahidiazar, Anoek Friskes, Liesbeth Hoekman, Onno B. Bleijerveld, Claire Hoencamp, Sarah Moser, Jos Jonkers, Kees Jalink, Wilbert Zwart, Patrick Celie, Benjamin D. Rowland, Anastassis Perrakis, Thijn R. Brummelkamp, René H. Medema
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Cell Reports
Verified
BRCA1 and BRCA2: from cancer susceptibility to synthetic lethality
1,2 1Division of Molecular Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; 2Oncode Institute, 3521 AL Utrecht, The Netherlands; 3Division of Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands Corresponding authors: j.jonkers{at}nki.nl, s.moser{at}nki.nl, r.j.p.bouwman{at}lacdr.leidenuniv.nl Footnotes Supplemental material is available for this article. Article published online ahead of print.
Mechanisms that clear mutations drive field cancerization in mammary tissue - Nature
Abstract Oncogenic mutations are abundant in the tissues of healthy individuals, but rarely form tumours1,2,3. Yet, the underlying protection mechanisms are largely unknown. To resolve these mechanisms in mouse mammary tissue, we use lineage tracing to map the fate of wild-type and Brca1−/−;Trp53−/− cells, and find that both follow a similar pattern of loss and spread within ducts.
H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours - Nature Communications
Abstract Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1.
Transcriptomic analysis of pubertal and adult virgin mouse mammary epithelial and stromal cell populations
Abstract Conflicting data exist as to how mammary epithelial cell proliferation changes during the reproductive cycle. To study the effect of endogenous hormone fluctuations on gene expression in the mouse mammary gland, we performed bulk RNAseq analyses of epithelial and stromal cell populations that were isolated either during puberty or at different stages of the adult virgin estrous cycle. Our data confirm prior findings that proliferative changes do not occur in every mouse in every cycle.
Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers - Nature Communications
Ethics statement Human breast tumour fragments were obtained with patients’ informed consent (Institute Curie) or approval of the Translational Research Board (Netherlands Cancer Institute). In vivo experimental procedures were approved by the Institutional Animal Care and French Committee (project authorization no. 02163.02) and Netherlands Cancer Institute animal experiments committee and were performed according to respective institutional regulations5.
Author Correction: Learning to distinguish progressive and non-progressive ductal carcinoma in situ - Nature Reviews Cancer
Correction to: Nature Reviews Cancer https://doi.org/10.1038/s41568-022-00512-y. Published online 19 October 2022. In the version of this article initially published, Charlotta Mulder was not named as an equal contributor with Anna K. Casasent and Mathilde M. Almekinders. The error has been corrected in the HTML and PDF versions of the article. Author information Author notes These authors contributed equally: Anna K. Casasent, Mathilde M. Almekinders, Charlotta Mulder.
Learning to distinguish progressive and non-progressive ductal carcinoma in situ - Nature Reviews Cancer
Cite this article Casasent, A.K., Almekinders, M.M., Mulder, C. et al. Learning to distinguish progressive and non-progressive ductal carcinoma in situ. Nat Rev Cancer (2022). https://doi.org/10.1038/s41568-022-00512-y Download citation Accepted: 07 September 2022 Published: 19 October 2022 DOI: https://doi.org/10.1038/s41568-022-00512-y Share this article Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article.
Publisher Correction: Truncated FGFR2 is a clinically actionable oncogene in multiple cancers - Nature
Correction to: Nature https://doi.org/10.1038/s41586-022-05066-5 Published online 10 August 2022 This paper was originally published under a standard Springer Nature license (© The Author(s), under exclusive licence to Springer Nature Limited). It is now available as an open-access paper under a Creative Commons Attribution 4.0 International license, © The Author(s). The error has been corrected in the HTML and PDF versions of the article.
Truncated FGFR2 is a clinically actionable oncogene in multiple cancers - Nature
Abstract Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1,2,3,4,5,6,7,8,9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable.
Abstract IA18: Genetic dissection of breast cancer development and therapy resistance in mouse models
Abstracts: AACR Special Conference on the Evolving Landscape of Cancer Modeling; March 2-5; San Diego, CA Abstract Genetically engineered mouse models (GEMMs) of human cancer not only permit us to gain a detailed insight into the specific genetic changes that drive tumor development and metastasis but also provide powerful tools to study the mechanisms underlying drug response and acquired resistance.
Abstract PHB04: Predictive modeling, applied to genetically engineered mouse models of breast or lung cancer, provides insights into major oncogenic pathways
Poster Highlights - Proffered Abstracts Julio Banga, Lucien Frappart, Jan Hasenauer, Yann Herault, Jos Jonkers, David Koubi, Bodo Lange, Glenn Terje Lines, Aspasia Plouidou and Oliver Rinner DOI: 10.1158/1538-7445.CAMODELS2020-PHB04 Published June 2020 Abstracts: AACR Special Conference on the Evolving Landscape of Cancer Modeling; March 2-5; San Diego, CA Abstract The H2020 project CanPathPro is building and validating a computational predictive modelling platform applied to cancer.
Prophylactic window therapy with the clinical PARP inhibitor olaparib delays BRCA1-deficient mammary tumour formation in mice
Women with heterozygous germline mutations in the BRCA1 tumour suppressor gene are strongly predisposed to developing early-onset breast cancer through loss of the remaining wild-type BRCA1 allele and inactivation of TP53. Although tumour prevention strategies in BRCA1-mutation carriers are still limited to prophylactic surgery, several therapeutic strategies have been developed to target the DNA repair defects (aka ‘BRCAness’) of BRCA1-deficient tumours.
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