274 results on '"van Rheenen, J."'
Search Results
52. Sterols and sterol biosynthesis in the slugAplysia depilans
- Author
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Voogt, P. A. and van Rheenen, J. W. A.
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- 1973
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53. On the Sterols of Some Ascidians.
- Author
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Voogt, P. A. and van Rheenen, J. W. A.
- Published
- 1975
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54. Commentaar op het bevolkingsallocatiemodel van het Onderzoek Midden Randstad
- Author
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van Rheenen, J. and van de Hoef, G.W.
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Life Science ,Instituut voor Cultuurtechniek en Waterhuishouding ,Institute for land and water management research - Published
- 1977
55. Onderzoek voorbereiding landinrichtingsprojecten werkwijze deeladviezen - schetsontwerp
- Author
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Dessing, N. and van Rheenen, J.
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plattelandsontwikkeling ,government ,land use ,netherlands ,Instituut voor Cultuurtechniek en Waterhuishouding ,landgebruik ,nederland ,plattelandsplanning ,participation ,ruimtelijke ordening ,physical planning ,Institute for land and water management research ,rural planning ,bedrijfsvoering ,management ,rural development ,participatie ,regering - Published
- 1983
56. Planvorming met behulp van agrarische evaluatie kriteria van de Werkgroep Help : een toepassing op het reconstructiegebied Midden-Delfland
- Author
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Jurgens, C.R., van Rheenen, J., and Meeuwse, M.
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economic impact ,zuid-holland ,netherlands ,landgebruik ,nederland ,use value ,economische impact ,Institute for land and water management research ,development ,bedrijfsvoering ,plattelandsontwikkeling ,land use ,economics ,Instituut voor Cultuurtechniek en Waterhuishouding ,plattelandsplanning ,beleid ,gebruikswaarde ,ruimtelijke ordening ,physical planning ,planning ,economie ,rural planning ,management ,rural development ,ontwikkeling ,policy - Published
- 1980
57. Het onderzoek Midden Randstad : overzicht en perspectief
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van Rheenen, J.
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plattelandsplanning ,plattelandsontwikkeling ,land use ,netherlands ,Instituut voor Cultuurtechniek en Waterhuishouding ,Institute for land and water management research ,rural planning ,bedrijfsvoering ,landgebruik ,management ,rural development ,nederland - Published
- 1978
58. Commentaar op de potentie-analyse en het competitiemodel van het onderzoek midden Randstad
- Author
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van Rheenen, J.
- Subjects
Life Science ,Instituut voor Cultuurtechniek en Waterhuishouding ,Institute for land and water management research - Published
- 1978
59. Negen landinrichtingsstudies, analyse en evaluatie van methoden
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van Rheenen, J. and Viveen - van den Bosch, M.
- Subjects
economic impact ,plattelandsontwikkeling ,land use ,netherlands ,economics ,Instituut voor Cultuurtechniek en Waterhuishouding ,landgebruik ,nederland ,use value ,plattelandsplanning ,economische impact ,gebruikswaarde ,Institute for land and water management research ,economie ,rural planning ,bedrijfsvoering ,management ,rural development - Published
- 1980
60. Commentaar op het recreatiemodel van het Onderzoek Midden-Randstad
- Author
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Brouwer, R.J. and van Rheenen, J.
- Subjects
Life Science ,Instituut voor Cultuurtechniek en Waterhuishouding ,Institute for land and water management research - Published
- 1977
61. Identity and dynamics of mammary stem cells during branching morphogenesis
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Scheele, CLGJ, Hannezo, E, Muraro, MJ, Zomer, A, Langedijk, NSM, Van Oudenaarden, A, Simons, BD, and Van Rheenen, J
- Subjects
Models, Molecular ,Stochastic Processes ,Gene Expression Profiling ,Stem Cells ,3. Good health ,Mice ,Mammary Glands, Animal ,Morphogenesis ,Animals ,Cell Lineage ,Female ,Sexual Maturation ,Single-Cell Analysis ,Cell Proliferation - Abstract
During puberty, the mouse mammary gland develops into a highly branched epithelial network. Owing to the absence of exclusive stem cell markers, the location, multiplicity, dynamics and fate of mammary stem cells (MaSCs), which drive branching morphogenesis, are unknown. Here we show that morphogenesis is driven by proliferative terminal end buds that terminate or bifurcate with near equal probability, in a stochastic and time-invariant manner, leading to a heterogeneous epithelial network. We show that the majority of terminal end bud cells function as highly proliferative, lineage-committed MaSCs that are heterogeneous in their expression profile and short-term contribution to ductal extension. Yet, through cell rearrangements during terminal end bud bifurcation, each MaSC is able to contribute actively to long-term growth. Our study shows that the behaviour of MaSCs is not directly linked to a single expression profile. Instead, morphogenesis relies upon lineage-restricted heterogeneous MaSC populations that function as single equipotent pools in the long term.
62. Studies on the possible regulatory function of asterosaponins in oocyte maturation and early embryogenesis ofAsterias rubens
- Author
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VOOGT, P. A., primary and VAN RHEENEN, J. W.A., additional
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- 1979
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63. An unanticipated tumor-suppressive role of the SUMO pathway in the intestine unveiled by Ubc9 haploinsufficiency
- Author
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Grégory Jouvion, Eleftheria Chalatsi, Ignacio López, Saskia I.J. Ellenbroek, Anne Dejean, Jacco van Rheenen, Alexandra Andrieux, Jacob-S. Seeler, Juan Pablo Cerapio, Pierre-François Roux, Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), The Netherlands Cancer Institute [Amsterdam, The Netherlands], Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris]-Université de Paris (UP), This work was supported by grants from INCa,LNCC (Equipe labellisée), Odyssey, ANR and ERC-AdG'SUMOS-TRESS'and'SUMiDENTITY'to AD, and by the Josef SteinerCancer Foundation and ERC-CoG'Cancer Recurrence'to JvR. ILwas supported by Fondation ARC (PDF20170505624), European Project: 294341,EC:FP7:ERC,ERC-2011-ADG_20110310,SUMOSTRESS(2013), European Project: 648804,H2020,ERC-2014-CoG,Cancer-Recurrence(2015), European Project: 832294, ERC-2018-ADG,SUMiDENTITY(2020), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), López Ferreira Luis Ignacio, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Biología., Chalatsi E., Ellenbroek S. I. J., Andrieux A., Roux P. F., Cerapio J. P., Jouvion G., van Rheenen J., Seeler J. S., and Dejean A.
- Subjects
0301 basic medicine ,Cancer Research ,Transgene ,Adenomatous Polyposis Coli Protein ,Primary Cell Culture ,SUMO protein ,Mice, Transgenic ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Haploinsufficiency ,Biology ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Intestinal Neoplasms ,Genetics ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Intestinal Mucosa ,Molecular Biology ,Cells, Cultured ,ComputingMilieux_MISCELLANEOUS ,LGR5 ,Sumoylation ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Fibroblasts ,Embryo, Mammalian ,Embryonic stem cell ,Colorectal cancer ,Cell biology ,Disease Models, Animal ,030104 developmental biology ,Cell Transformation, Neoplastic ,Cell culture ,030220 oncology & carcinogenesis ,Cancer cell ,Ubiquitin-Conjugating Enzymes ,Small Ubiquitin-Related Modifier Proteins ,Stem cell ,Signal Transduction - Abstract
Sumoylation is an essential posttranslational modification in eukaryotes that has emerged as an important pathway in oncogenic processes. Most human cancers display hyperactivated sumoylation and many cancer cells are remarkably sensitive to its inhibition, thus supporting application of chemical sumoylation inhibitors in cancer treatment. Here we show, first, that transformed embryonic fibroblasts derived from mice haploinsufficient for Ubc9, the essential and unique gene encoding the SUMO E2 conjugating enzyme, exhibit enhanced proliferation and transformed phenotypes in vitro and as xenografts ex vivo. To then evaluate the possible impact of loss of one Ubc9 allele in vivo, we used a mouse model of intestinal tumorigenesis. We crossed Ubc9+/− mice with mice harboring a conditional ablation of Apc either all along the crypt–villus axis or only in Lgr5+ crypt-based columnar (CBC) cells, the cell compartment that includes the intestinal stem cells proposed as cells-of-origin of intestinal cancer. While Ubc9+/− mice display no overt phenotypes and no globally visible hyposumoylation in cells of the small intestine, we found, strikingly, that, upon loss of Apc in both models, Ubc9+/− mice develop more (>2-fold) intestinal adenomas and show significantly shortened survival. This is accompanied by reduced global sumoylation levels in the polyps, indicating that Ubc9 levels become critical upon oncogenic stress. Moreover, we found that, in normal conditions, Ubc9+/− mice show a moderate but robust (15%) increase in the number of Lgr5+ CBC cells when compared to their wild-type littermates, and further, that these cells display higher degree of stemness and cancer-related and inflammatory gene expression signatures that, altogether, may contribute to enhanced intestinal tumorigenesis. The phenotypes of Ubc9 haploinsufficiency discovered here indicate an unanticipated tumor-suppressive role of sumoylation, one that may have important implications for optimal use of sumoylation inhibitors in the clinic.
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64. Mechanisms that clear mutations drive field cancerization in mammary tissue.
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Ciwinska M, Messal HA, Hristova HR, Lutz C, Bornes L, Chalkiadakis T, Harkes R, Langedijk NSM, Hutten SJ, Menezes RX, Jonkers J, Prekovic S, Simons BD, Scheele CLGJ, and van Rheenen J
- Subjects
- Animals, Female, Mice, BRCA1 Protein deficiency, BRCA1 Protein genetics, BRCA1 Protein metabolism, Cell Lineage genetics, Cell Self Renewal genetics, Clone Cells cytology, Clone Cells metabolism, Clone Cells pathology, Tumor Suppressor Protein p53 deficiency, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Estrous Cycle, Stem Cells cytology, Stem Cells metabolism, Stem Cells pathology, Cell Transformation, Neoplastic genetics, Mammary Glands, Animal cytology, Mammary Glands, Animal pathology, Mammary Glands, Animal metabolism, Mutation
- Abstract
Oncogenic mutations are abundant in the tissues of healthy individuals, but rarely form tumours
1-3 . 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. Clonal analysis reveals that ducts consist of small repetitive units of self-renewing cells that give rise to short-lived descendants. This offers a first layer of protection as any descendants, including oncogenic mutant cells, are constantly lost, thereby limiting the spread of mutations to a single stem cell-descendant unit. Local tissue remodelling during consecutive oestrous cycles leads to the cooperative and stochastic loss and replacement of self-renewing cells. This process provides a second layer of protection, leading to the elimination of most mutant clones while enabling the minority that by chance survive to expand beyond the stem cell-descendant unit. This leads to fields of mutant cells spanning large parts of the epithelial network, predisposing it for transformation. Eventually, clone expansion becomes restrained by the geometry of the ducts, providing a third layer of protection. Together, these mechanisms act to eliminate most cells that acquire somatic mutations at the expense of driving the accelerated expansion of a minority of cells, which can colonize large areas, leading to field cancerization., (© 2024. The Author(s).)- Published
- 2024
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65. Nucleocytoplasmic transport senses mechanical forces independently of cell density in cell monolayers.
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Granero-Moya I, Venturini V, Belthier G, Groenen B, Molina-Jordán M, González-Martín M, Trepat X, van Rheenen J, Andreu I, and Roca-Cusachs P
- Subjects
- Cell Count, Animals, YAP-Signaling Proteins metabolism, Humans, Dogs, Mechanotransduction, Cellular, Active Transport, Cell Nucleus physiology, Cell Nucleus metabolism
- Abstract
Cells sense and respond to mechanical forces through mechanotransduction, which regulates processes in health and disease. In single adhesive cells, mechanotransduction involves the transmission of force from the extracellular matrix to the cell nucleus, where it affects nucleocytoplasmic transport (NCT) and the subsequent nuclear localization of transcriptional regulators, such as YAP (also known as YAP1). However, if and how NCT is mechanosensitive in multicellular systems is unclear. Here, we characterize and use a fluorescent sensor of nucleocytoplasmic transport (Sencyt) and demonstrate that NCT responds to mechanical forces but not cell density in cell monolayers. Using monolayers of both epithelial and mesenchymal phenotype, we show that NCT is altered in response both to osmotic shocks and to the inhibition of cell contractility. Furthermore, NCT correlates with the degree of nuclear deformation measured through nuclear solidity, a shape parameter related to nuclear envelope tension. In contrast, YAP is sensitive to cell density, showing that the YAP response to cell-cell contacts is not via a mere mechanical effect of NCT. Our results demonstrate the generality of the mechanical regulation of NCT., (© 2024. Published by The Company of Biologists Ltd.)
- Published
- 2024
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66. Tumour microenvironment characterisation to stratify patients for hyperthermic intraperitoneal chemotherapy in high-grade serous ovarian cancer (OVHIPEC-1).
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Aronson SL, Walker C, Thijssen B, van de Vijver KK, Horlings HM, Sanders J, Alkemade M, Koole SN, Lopez-Yurda M, Lok CAR, Rottenberg S, van Rheenen J, Sonke GS, van Driel WJ, Kester LA, and Hahn K
- Subjects
- Humans, Female, Middle Aged, Cystadenocarcinoma, Serous pathology, Cystadenocarcinoma, Serous therapy, Cystadenocarcinoma, Serous drug therapy, Aged, Biomarkers, Tumor genetics, Biomarkers, Tumor analysis, Macrophages pathology, Macrophages metabolism, Ovarian Neoplasms pathology, Ovarian Neoplasms therapy, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Hyperthermic Intraperitoneal Chemotherapy methods, Tumor Microenvironment, Cytoreduction Surgical Procedures
- Abstract
Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival in patients with Stage III ovarian cancer following interval cytoreductive surgery (CRS). Optimising patient selection is essential to maximise treatment efficacy and avoid overtreatment. This study aimed to identify biomarkers that predict HIPEC benefit by analysing gene signatures and cellular composition of tumours from participants in the OVHIPEC-1 trial., Methods: Whole-transcriptome RNA sequencing data were retrieved from high-grade serous ovarian cancer (HGSOC) samples from 147 patients obtained during interval CRS. We performed differential gene expression analysis and applied deconvolution methods to estimate cell-type proportions in bulk mRNA data, validated by histological assessment. We tested the interaction between treatment and potential predictors on progression-free survival using Cox proportional hazards models., Results: While differential gene expression analysis did not yield any predictive biomarkers, the cellular composition, as characterised by deconvolution, indicated that the absence of macrophages and the presence of B cells in the tumour microenvironment are potential predictors of HIPEC benefit. The histological assessment confirmed the predictive value of macrophage absence., Conclusion: Immune cell composition, in particular macrophages absence, may predict response to HIPEC in HGSOC and these hypothesis-generating findings warrant further investigation., Clinical Trial Registration: NCT00426257., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2024
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67. Ductal carcinoma in situ develops within clonal fields of mutant cells in morphologically normal ducts.
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Hutten SJ, Messal HA, Lips EH, Sheinman M, Ciwinska M, Braams E, van der Borden C, Kristel P, Stoffers S, Wessels LF, Jonkers J, van Rheenen J, Wesseling J, and Scheele CL
- Subjects
- Humans, Female, Imaging, Three-Dimensional, Precancerous Conditions genetics, Precancerous Conditions pathology, Clone Cells, Carcinoma, Intraductal, Noninfiltrating genetics, Carcinoma, Intraductal, Noninfiltrating pathology, Breast Neoplasms genetics, Breast Neoplasms pathology, Mutation, DNA Copy Number Variations
- Abstract
Mutations are abundantly present in tissues of healthy individuals, including the breast epithelium. Yet it remains unknown whether mutant cells directly induce lesion formation or first spread, leading to a field of mutant cells that is predisposed towards lesion formation. To study the clonal and spatial relationships between morphologically normal breast epithelium adjacent to pre-cancerous lesions, we developed a three-dimensional (3D) imaging pipeline combined with spatially resolved genomics on archival, formalin-fixed breast tissue with the non-obligate breast cancer precursor ductal carcinoma in situ (DCIS). Using this 3D image-guided characterization method, we built high-resolution spatial maps of DNA copy number aberration (CNA) profiles within the DCIS lesion and the surrounding normal mammary ducts. We show that the local heterogeneity within a DCIS lesion is limited. However, by mapping the CNA profiles back onto the 3D reconstructed ductal subtree, we find that in eight out of 16 cases the healthy epithelium adjacent to the DCIS lesions has overlapping structural variations with the CNA profile of the DCIS. Together, our study indicates that pre-malignant breast transformations frequently develop within mutant clonal fields of morphologically normal-looking ducts. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)
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- 2024
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68. Predictive gene expression profile for adjuvant taxane benefit in breast cancer in the MATADOR trial.
- Author
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Opdam M, van Rossum AGJ, Hoogstraat M, Bounova G, Horlings HM, van Werkhoven E, Mandjes IAM, van Leeuwen-Stok AE, Canisius S, van Tinteren H, Imholz ALT, Portielje JEA, Bos MEMM, Bakker S, Wesseling J, Kester L, van Rheenen J, Rutgers EJ, de Menezes RX, Wessels LFA, Kok M, Oosterkamp HM, and Linn SC
- Abstract
The primary objective of the prospective, randomized, multicenter, phase 3 biomarker Microarray Analysis in breast cancer to Taylor Adjuvant Drugs Or Regimens trial (MATADOR: ISRCTN61893718) is to generate a gene expression profile that can predict benefit from either docetaxel, doxorubicin, and cyclophosphamide (TAC) or dose-dense scheduled doxorubicin and cyclophosphamide (ddAC). Patients with a pT1-3, pN0-3 tumor were randomized 1:1 between ddAC and TAC. The primary endpoint was a gene profile-treatment interaction for recurrence-free survival (RFS). We observed 117 RFS events in 664 patients with a median follow-up of 7 years. Hallmark gene set analyses showed significant association between enrichment in immune-related gene expression and favorable outcome after TAC in hormone receptor-negative, human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) (triple-negative breast cancer [TNBC]). We validated this association in TNBC patients treated with TAC on H&E slides; stromal tumor-infiltrating lymphocytes (sTILs) ≥20% was associated with longer RFS (hazard ratio 0.18, p = 0.01), while in patients treated with ddAC no difference in RFS was seen (hazard ratio 0.92, p = 0.86, p
interaction = 0.02)., Competing Interests: S.C.L. and H.M.O. received an institutional unrestricted research grant from Sanofi and Amgen to conduct the MATADOR study (ISRCTN61893718); H.M.O. received institutional research support funding from Roche; M.K. received institutional research support funding from Roche, BMS, and AZ; S.C.L. received institutional research support funding from Agendia, Amgen, AstraZeneca, Eurocept, Genentech, Immunomedics (now Gilead), Roche, Sanofi, and TESARO (now GSK). S.C.L. is an advisory board member for AstraZeneca for which the institute receives compensation, and for Cergentis (pro bono). S.C.L. receives funding for educational activities from Daiichi Sankyo, paid to the institute. H.M.O. is an advisory board member for Roche, Pfizer, and Novartis. M.K. is an advisory board member for AZ, BMS, Roche, MSD, and Daiichi for which the institute receives compensation., (© 2024 The Authors.)- Published
- 2024
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69. Epidemiology and preventability of hospital-onset bacteremia and fungemia in 2 hospitals in India.
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Gandra S, Singh SK, Chakravarthy M, Moni M, Dhekane P, Mohamed Z, Shameen F, Vasudevan AK, Senthil P, Saravanan T, George A, Sinclair D, Stwalley D, van Rheenen J, Westercamp M, Smith RM, Leekha S, and Warren DK
- Subjects
- Humans, Retrospective Studies, Hospitals, Fungemia epidemiology, Fungemia prevention & control, Catheter-Related Infections epidemiology, Bacteremia epidemiology, Bacteremia prevention & control, Cross Infection epidemiology, Cross Infection prevention & control, Sepsis epidemiology, Catheterization, Central Venous
- Abstract
Objective: Studies evaluating the incidence, source, and preventability of hospital-onset bacteremia and fungemia (HOB), defined as any positive blood culture obtained after 3 calendar days of hospital admission, are lacking in low- and middle-income countries (LMICs)., Design, Setting, and Participants: All consecutive blood cultures performed for 6 months during 2020-2021 in 2 hospitals in India were reviewed to assess HOB and National Healthcare Safety Network (NHSN) reportable central-line-associated bloodstream infection (CLABSI) events. Medical records of a convenience sample of 300 consecutive HOB events were retrospectively reviewed to determine source and preventability. Univariate and multivariable logistic regression analyses were performed to identify factors associated with HOB preventability., Results: Among 6,733 blood cultures obtained from 3,558 hospitalized patients, there were 409 and 59 unique HOB and NHSN-reportable CLABSI events, respectively. CLABSIs accounted for 59 (14%) of 409 HOB events. There was a moderate but non-significant correlation (r = 0.51; P = .070) between HOB and CLABSI rates. Among 300 reviewed HOB cases, CLABSIs were identified as source in only 38 (13%). Although 157 (52%) of all 300 HOB cases were potentially preventable, CLABSIs accounted for only 22 (14%) of these 157 preventable HOB events. In multivariable analysis, neutropenia, and sepsis as an indication for blood culture were associated with decreased odds of HOB preventability, whereas hospital stay ≥7 days and presence of a urinary catheter were associated with increased likelihood of preventability., Conclusions: HOB may have utility as a healthcare-associated infection metric in LMIC settings because it captures preventable bloodstream infections beyond NHSN-reportable CLABSIs.
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- 2024
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70. BCRP drives intrinsic chemoresistance in chemotherapy-naïve breast cancer brain metastasis.
- Author
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Uceda-Castro R, Margarido AS, Song JY, de Gooijer MC, Messal HA, Chambers CR, Nobis M, Çitirikkaya CH, Hahn K, Seinstra D, Herrmann D, Timpson P, Wesseling P, van Tellingen O, Vennin C, and van Rheenen J
- Subjects
- Animals, Female, Mice, ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics, ATP-Binding Cassette Transporters genetics, ATP-Binding Cassette Transporters metabolism, Drug Resistance, Neoplasm genetics, Endothelial Cells metabolism, Neoplasm Proteins metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Brain Neoplasms drug therapy, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms metabolism
- Abstract
Although initially successful, treatments with chemotherapy often fail because of the recurrence of chemoresistant metastases. Since these tumors develop after treatment, resistance is generally thought to occur in response to chemotherapy. However, alternative mechanisms of intrinsic chemoresistance in the chemotherapy-naïve setting may exist but remain poorly understood. Here, we study drug-naïve murine breast cancer brain metastases (BCBMs) to identify how cancer cells growing in a secondary site can acquire intrinsic chemoresistance without cytotoxic agent exposure. We demonstrate that drug-naïve murine breast cancer cells that form cancer lesions in the brain undergo vascular mimicry and concomitantly express the adenosine 5'-triphosphate-binding cassette transporter breast cancer resistance protein (BCRP), a common marker of brain endothelial cells. We reveal that expression of BCRP by the BCBM tumor cells protects them against doxorubicin and topotecan. We conclude that BCRP overexpression can cause intrinsic chemoresistance in cancer cells growing in metastatic sites without prior chemotherapy exposure.
- Published
- 2023
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71. Taxanes trigger cancer cell killing in vivo by inducing non-canonical T cell cytotoxicity.
- Author
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Vennin C, Cattaneo CM, Bosch L, Vegna S, Ma X, Damstra HGJ, Martinovic M, Tsouri E, Ilic M, Azarang L, van Weering JRT, Pulver E, Zeeman AL, Schelfhorst T, Lohuis JO, Rios AC, Dekkers JF, Akkari L, Menezes R, Medema R, Baglio SR, Akhmanova A, Linn SC, Lemeer S, Pegtel DM, Voest EE, and van Rheenen J
- Subjects
- Humans, T-Lymphocytes, Taxoids pharmacology, Apoptosis, Epithelial Cells, Extracellular Vesicles, Neoplasms drug therapy
- Abstract
Although treatment with taxanes does not always lead to clinical benefit, all patients are at risk of their detrimental side effects such as peripheral neuropathy. Understanding the in vivo mode of action of taxanes can help design improved treatment regimens. Here, we demonstrate that in vivo, taxanes directly trigger T cells to selectively kill cancer cells in a non-canonical, T cell receptor-independent manner. Mechanistically, taxanes induce T cells to release cytotoxic extracellular vesicles, which lead to apoptosis specifically in tumor cells while leaving healthy epithelial cells intact. We exploit these findings to develop an effective therapeutic approach, based on transfer of T cells pre-treated with taxanes ex vivo, thereby avoiding toxicity of systemic treatment. Our study reveals a different in vivo mode of action of one of the most commonly used chemotherapies, and opens avenues to harness T cell-dependent anti-tumor effects of taxanes while avoiding systemic toxicity., Competing Interests: Declaration of interests J.F.D. is named as inventor on a patent related to organoid technology. C.V., J.vR. and S.C.L. are named as inventors on a patent related to taxane treatment of T cells. The authors have no other competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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72. Laser Ablation and Intravital Microscopy to Study Intestinal Remodeling.
- Author
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Laskaris D, Azkanaz M, de Vreij-Kruidenier MA, van Rijswoud-Ram D, Messal HA, and van Rheenen J
- Subjects
- Mice, Animals, Intravital Microscopy, Intestinal Mucosa, Laser Therapy
- Abstract
Investigating intestinal recovery in vivo is an exquisite technical challenge. A lack of longitudinal imaging protocols has prevented deeper insights into the cell and tissue scale dynamics that orchestrate intestinal regeneration. Here, we describe an intravital microscopy method that locally induces tissue damage at the single crypt scale and follows the regenerative response of the intestinal epithelium in living mice. Single crypts or larger intestinal fields were ablated by a high-intensity multiphoton infrared laser in a time- and space-controlled manner. Subsequent long-term repetitive intravital imaging enabled the tracking of the damaged areas over time and allowed for the monitoring of crypt dynamics during tissue recovery over a period of multiple weeks. Crypt remodeling events such as crypt fission, fusion, and disappearance were observed in the neighboring tissue upon laser-induced damage. This protocol enables the study of crypt dynamics both in homeostatic and pathophysiological settings, such as aging and tumor initiation.
- Published
- 2023
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73. A living biobank of patient-derived ductal carcinoma in situ mouse-intraductal xenografts identifies risk factors for invasive progression.
- Author
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Hutten SJ, de Bruijn R, Lutz C, Badoux M, Eijkman T, Chao X, Ciwinska M, Sheinman M, Messal H, Herencia-Ropero A, Kristel P, Mulder L, van der Waal R, Sanders J, Almekinders MM, Llop-Guevara A, Davies HR, van Haren MJ, Martin NI, Behbod F, Nik-Zainal S, Serra V, van Rheenen J, Lips EH, Wessels LFA, Wesseling J, Scheele CLGJ, and Jonkers J
- Subjects
- Humans, Animals, Mice, Female, Biological Specimen Banks, Heterografts, Biomarkers, Tumor genetics, Risk Factors, Disease Progression, Carcinoma, Intraductal, Noninfiltrating genetics, Carcinoma, Intraductal, Noninfiltrating pathology, Breast Neoplasms genetics, Breast Neoplasms pathology
- Abstract
Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer (IBC). Due to a lack of biomarkers able to distinguish high- from low-risk cases, DCIS is treated similar to early IBC even though the minority of untreated cases eventually become invasive. Here, we characterized 115 patient-derived mouse-intraductal (MIND) DCIS models reflecting the full spectrum of DCIS observed in patients. Utilizing the possibility to follow the natural progression of DCIS combined with omics and imaging data, we reveal multiple prognostic factors for high-risk DCIS including high grade, HER2 amplification, expansive 3D growth, and high burden of copy number aberrations. In addition, sequential transplantation of xenografts showed minimal phenotypic and genotypic changes over time, indicating that invasive behavior is an intrinsic phenotype of DCIS and supporting a multiclonal evolution model. Moreover, this study provides a collection of 19 distributable DCIS-MIND models spanning all molecular subtypes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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74. Multidimensional Imaging of Breast Cancer.
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Rios AC, van Rheenen J, and Scheele CLGJ
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- Humans, Female, Diagnostic Imaging, Tumor Microenvironment, Breast Neoplasms diagnostic imaging, Breast Neoplasms metabolism, Breast Neoplasms pathology
- Abstract
Breast cancer is a pathological condition characterized by high morphological and molecular heterogeneity. Not only the breast cancer cells, but also their tumor micro-environment consists of a multitude of cell types and states, which continuously evolve throughout progression of the disease. To understand breast cancer evolution within this complex environment, in situ analysis of breast cancer and their co-evolving cells and structures in space and time are essential. In this review, recent technical advances in three-dimensional (3D) and intravital imaging of breast cancer are discussed. Moreover, we highlight the resulting new knowledge on breast cancer biology obtained through these innovative imaging technologies. Finally, we discuss how multidimensional imaging technologies can be integrated with molecular profiling to understand the full complexity of breast cancer and the tumor micro-environment during tumor progression and treatment response., (Copyright © 2023 Cold Spring Harbor Laboratory Press; all rights reserved.)
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- 2023
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75. A Lamb1Dendra2 mouse model identifies basement-membrane-producing origins and dynamics in PyMT breast tumors.
- Author
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Morgner J, Bornes L, Hahn K, López-Iglesias C, Kroese L, Pritchard CEJ, Vennin C, Peters PJ, Huijbers I, and van Rheenen J
- Subjects
- Animals, Female, Humans, Mice, Basement Membrane, Endothelial Cells, Epithelial Cells, Disease Models, Animal, Breast Neoplasms pathology, Laminin
- Abstract
The basement membrane (BM) around tumor lobes forms a barrier to prevent cancer cells from invading the surrounding tissue. Although myoepithelial cells are key producers of the healthy mammary epithelium BM, they are nearly absent in mammary tumors. To study the origin and dynamics of the BM, we developed and imaged a laminin beta1-Dendra2 mouse model. We show that the turnover of laminin beta1 is faster in the BMs that surround the tumor lobes than in the BMs that surround the healthy epithelium. Moreover, we find that epithelial cancer cells and tumor-infiltrating endothelial cells synthesize laminin beta1 and that this production is temporarily and locally heterogeneous, leading to local discontinuity of the BM laminin beta1. Collectively, our data draw a new paradigm for tumor BM turnover in which the disassembly happens at a constant rate, and a local misbalance of compensating production leads to reduction or even complete disappearance of the BM., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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76. Subtype-specific kinase dependency regulates growth and metastasis of poor-prognosis mesenchymal colorectal cancer.
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Buikhuisen JY, Gomez Barila PM, Cameron K, Suijkerbuijk SJE, Lieftink C, di Franco S, Krotenberg Garcia A, Uceda Castro R, Lenos KJ, Nijman LE, Torang A, Longobardi C, de Jong JH, Dekker D, Stassi G, Vermeulen L, Beijersbergen RL, van Rheenen J, Huveneers S, and Medema JP
- Subjects
- Humans, Actin Cytoskeleton, Carcinogenesis, Cell Line, Sarcoma, Colorectal Neoplasms
- Abstract
Background: Colorectal cancer (CRC) can be divided into four consensus molecular subtypes (CMS), each with distinct biological features. CMS4 is associated with epithelial-mesenchymal transition and stromal infiltration (Guinney et al., Nat Med 21:1350-6, 2015; Linnekamp et al., Cell Death Differ 25:616-33, 2018), whereas clinically it is characterized by lower responses to adjuvant therapy, higher incidence of metastatic spreading and hence dismal prognosis (Buikhuisen et al., Oncogenesis 9:66, 2020)., Methods: To understand the biology of the mesenchymal subtype and unveil specific vulnerabilities, a large CRISPR-Cas9 drop-out screen was performed on 14 subtyped CRC cell lines to uncover essential kinases in all CMSs. Dependency of CMS4 cells on p21-activated kinase 2 (PAK2) was validated in independent 2D and 3D in vitro cultures and in vivo models assessing primary and metastatic outgrowth in liver and peritoneum. TIRF microscopy was used to uncover actin cytoskeleton dynamics and focal adhesion localization upon PAK2 loss. Subsequent functional assays were performed to determine altered growth and invasion patterns., Results: PAK2 was identified as a key kinase uniquely required for growth of the mesenchymal subtype CMS4, both in vitro and in vivo. PAK2 plays an important role in cellular attachment and cytoskeletal rearrangements (Coniglio et al., Mol Cell Biol 28:4162-72, 2008; Grebenova et al., Sci Rep 9:17171, 2019). In agreement, deletion or inhibition of PAK2 impaired actin cytoskeleton dynamics in CMS4 cells and, as a consequence, significantly reduced invasive capacity, while it was dispensable for CMS2 cells. Clinical relevance of these findings was supported by the observation that deletion of PAK2 from CMS4 cells prevented metastatic spreading in vivo. Moreover, growth in a model for peritoneal metastasis was hampered when CMS4 tumor cells were deficient for PAK2., Conclusion: Our data reveal a unique dependency of mesenchymal CRC and provide a rationale for PAK2 inhibition to target this aggressive subgroup of colorectal cancer., (© 2023. The Author(s).)
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- 2023
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77. Author Correction: Learning to distinguish progressive and non-progressive ductal carcinoma in situ.
- Author
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Casasent AK, Almekinders MM, Mulder C, Bhattacharjee P, Collyar D, Thompson AM, Jonkers J, Lips EH, van Rheenen J, Hwang ES, Nik-Zainal S, Navin NE, and Wesseling J
- Published
- 2023
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78. Author Correction: Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features.
- Author
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Flanagan DJ, Amirkhah R, Vincent DF, Gunduz N, Gentaz P, Cammareri P, McCooey AJ, McCorry AMB, Fisher NC, Davis HL, Ridgway RA, Lohuis J, Leach JDG, Jackstadt R, Gilroy K, Mariella E, Nixon C, Clark W, Hedley A, Markert EK, Strathdee D, Bartholin L, Redmond KL, Kerr EM, Longley DB, Ginty F, Cho S, Coleman HG, Loughrey MB, Bardelli A, Maughan TS, Campbell AD, Lawler M, Leedham SJ, Barry ST, Inman GJ, van Rheenen J, Dunne PD, and Sansom OJ
- Published
- 2023
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79. Coordinated cancer chaos.
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Messal HA and van Rheenen J
- Subjects
- Humans, Tumor Microenvironment, Nonlinear Dynamics, Neoplasms genetics, Neoplasms pathology
- Abstract
Stochastic processes, such as genetic instability and microenvironment evolution, drive tumor heterogeneity, thereby creating the chaotic appearance of tumors in histopathology. In this issue of Cell, Lin et al. reveal that tumors are surprisingly spatially organized from a molecular to tissue scale, indicating that cancers evolve as autonomously patterned systems., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2023
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80. Remote Global Radiation Oncology Education and Training: A Pathway to Increase Access to High-Quality Radiation Therapy Services in Low- and Middle-Income Countries.
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Kavuma A, Kibudde S, Schmidt M, Zhao T, Gay H, Li B, Michalski J, Hugo G, Vanchinbazar E, Minjgee M, Nansalmaa E, Ssewamala F, Velarde A, De Fella V, Ixquiac M, Henke L, van Rheenen J, and Sun B
- Abstract
Purpose: There is a vital need to train radiation therapy professionals in low- and middle-income countries (LMICs) to develop sustainable cancer treatment capacity and infrastructure. LMICs have started to introduce intensity modulated radiation therapy (IMRT), which is the standard of care in high-income countries, because of improved outcomes and reduced toxicities. This work reports the efficacy of a complementary asynchronous plus synchronous virtual-training approach on improving radiation therapy professions' self-confidence levels and evaluating participants' attitudes toward asynchronous and synchronous didactic hands-on learning in 3 LMICs., Methods and Materials: Training was provided to 37 participants from Uganda, Guatemala, and Mongolia, which included 4 theoretical lectures, 4 hands-on sessions, and 8 self-guided online videos. The 36-day training focused on IMRT contouring, site-specific target/organ definition, planning/optimization, and quality assurance. Participants completed pre- and postsession confidence surveys on a 0 to 10 scale, which was converted to a 5-point Likert rating scale to evaluate the training outcomes. The pros and cons of the 3 different training formats were compared., Results: The participants included 15 (40.5%) radiation oncologists, 11 (29.7%) medical physicists, 6 (16.2%) radiation therapists, and 5 (13.5%) dosimetrists. Approximately 50% had more than 10 years of radiation therapy experience, 70.8% had no formal IMRT training, and only 25% had IMRT at their institutions. The average experience and confidence levels in using IMRT at baseline were 3.2 and 2.9, which increased to 5.2 and 4.9 ( P < .001) after the theoretical training. After the hands-on training, the experience and confidence levels further improved to 5.4 and 5.5 ( P < .001). After the self-guided training, the confidence levels increased further to 6.9 ( P < .01). Among the 3 different training sessions, hands-on trainings (58.3%) were most helpful for the development of participants' IMRT skills, followed by theoretical sessions with 25%., Conclusions: After completing the training sessions, Uganda and Mongolia started IMRT treatments. Remote training provides an excellent and feasible e-learning platform to train radiation therapy professionals in LMICs. The training program improved the IMRT confidence levels and treatment delivery. The hands-on trainings were most preferred., (© 2023 The Authors.)
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- 2023
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81. Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features.
- Author
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Flanagan DJ, Amirkhah R, Vincent DF, Gunduz N, Gentaz P, Cammareri P, McCooey AJ, McCorry AMB, Fisher NC, Davis HL, Ridgway RA, Lohuis J, Leach JDG, Jackstadt R, Gilroy K, Mariella E, Nixon C, Clark W, Hedley A, Markert EK, Strathdee D, Bartholin L, Redmond KL, Kerr EM, Longley DB, Ginty F, Cho S, Coleman HG, Loughrey MB, Bardelli A, Maughan TS, Campbell AD, Lawler M, Leedham SJ, Barry ST, Inman GJ, van Rheenen J, Dunne PD, and Sansom OJ
- Subjects
- Humans, Transforming Growth Factor beta, Apoptosis genetics
- Abstract
The pro-tumourigenic role of epithelial TGFβ signalling in colorectal cancer (CRC) is controversial. Here, we identify a cohort of born to be bad early-stage (T1) colorectal tumours, with aggressive features and a propensity to disseminate early, that are characterised by high epithelial cell-intrinsic TGFβ signalling. In the presence of concurrent Apc and Kras mutations, activation of epithelial TGFβ signalling rampantly accelerates tumourigenesis and share transcriptional signatures with those of the born to be bad T1 human tumours and predicts recurrence in stage II CRC. Mechanistically, epithelial TGFβ signalling induces a growth-promoting EGFR-signalling module that synergises with mutant APC and KRAS to drive MAPK signalling that re-sensitise tumour cells to MEK and/or EGFR inhibitors. Together, we identify epithelial TGFβ signalling both as a determinant of early dissemination and a potential therapeutic vulnerability of CRC's with born to be bad traits., (© 2022. The Author(s).)
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- 2022
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82. Learning to distinguish progressive and non-progressive ductal carcinoma in situ.
- Author
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Casasent AK, Almekinders MM, Mulder C, Bhattacharjee P, Collyar D, Thompson AM, Jonkers J, Lips EH, van Rheenen J, Hwang ES, Nik-Zainal S, Navin NE, and Wesseling J
- Subjects
- Humans, Female, Tumor Microenvironment, Carcinoma, Intraductal, Noninfiltrating diagnosis, Carcinoma, Intraductal, Noninfiltrating genetics, Carcinoma, Intraductal, Noninfiltrating pathology, Breast Neoplasms diagnosis, Breast Neoplasms genetics, Breast Neoplasms pathology
- Abstract
Ductal carcinoma in situ (DCIS) is a non-invasive breast neoplasia that accounts for 25% of all screen-detected breast cancers diagnosed annually. Neoplastic cells in DCIS are confined to the ductal system of the breast, although they can escape and progress to invasive breast cancer in a subset of patients. A key concern of DCIS is overtreatment, as most patients screened for DCIS and in whom DCIS is diagnosed will not go on to exhibit symptoms or die of breast cancer, even if left untreated. However, differentiating low-risk, indolent DCIS from potentially progressive DCIS remains challenging. In this Review, we summarize our current knowledge of DCIS and explore open questions about the basic biology of DCIS, including those regarding how genomic events in neoplastic cells and the surrounding microenvironment contribute to the progression of DCIS to invasive breast cancer. Further, we discuss what information will be needed to prevent overtreatment of indolent DCIS lesions without compromising adequate treatment for high-risk patients., (© 2022. Springer Nature Limited.)
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- 2022
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83. Mother cells control daughter cell proliferation in intestinal organoids to minimize proliferation fluctuations.
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Huelsz-Prince G, Kok RNU, Goos Y, Bruens L, Zheng X, Ellenbroek S, Van Rheenen J, Tans S, and van Zon JS
- Subjects
- Animals, Mice, Intestines, Cell Proliferation, Cell Differentiation, Organoids, Stem Cells
- Abstract
During renewal of the intestine, cells are continuously generated by proliferation. Proliferation and differentiation must be tightly balanced, as any bias toward proliferation results in uncontrolled exponential growth. Yet, the inherently stochastic nature of cells raises the question how such fluctuations are limited. We used time-lapse microscopy to track all cells in crypts of growing mouse intestinal organoids for multiple generations, allowing full reconstruction of the underlying lineage dynamics in space and time. Proliferative behavior was highly symmetric between sister cells, with both sisters either jointly ceasing or continuing proliferation. Simulations revealed that such symmetric proliferative behavior minimizes cell number fluctuations, explaining our observation that proliferating cell number remained constant even as crypts increased in size considerably. Proliferative symmetry did not reflect positional symmetry but rather lineage control through the mother cell. Our results indicate a concrete mechanism to balance proliferation and differentiation with minimal fluctuations that may be broadly relevant for other tissues., Competing Interests: GH, RK, YG, LB, XZ, SE, JV, ST, Jv No competing interests declared, (© 2022, Huelsz-Prince et al.)
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- 2022
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84. Re-purposing the pro-senescence properties of doxorubicin to introduce immunotherapy in breast cancer brain metastasis.
- Author
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Uceda-Castro R, Margarido AS, Cornet L, Vegna S, Hahn K, Song JY, Putavet DA, van Geldorp M, Çitirikkaya CH, de Keizer PLJ, Ter Beek LC, Borst GR, Akkari L, van Tellingen O, Broekman MLD, Vennin C, and van Rheenen J
- Subjects
- Humans, Female, Doxorubicin pharmacology, Immunotherapy, Tumor Microenvironment, Breast Neoplasms drug therapy, Brain Neoplasms drug therapy
- Abstract
An increasing number of breast cancer patients develop brain metastases (BM). Standard-of-care treatments are largely inefficient, and breast cancer brain metastasis (BCBM) patients are considered untreatable. Immunotherapies are not successfully employed in BCBM, in part because breast cancer is a "cold" tumor and also because the brain tissue has a unique immune landscape. Here, we generate and characterize immunocompetent models of BCBM derived from PyMT and Neu mammary tumors to test how harnessing the pro-senescence properties of doxorubicin can be used to prime the specific immune BCBM microenvironment. We reveal that BCBM senescent cells, induced by doxorubicin, trigger the recruitment of PD1-expressing T cells to the brain. Importantly, we demonstrate that induction of senescence with doxorubicin improves the efficacy of immunotherapy with anti-PD1 in BCBM in a CD8 T cell-dependent manner, thereby providing an optimized strategy to introduce immune-based treatments in this lethal disease. In addition, our BCBM models can be used for pre-clinical testing of other therapeutic strategies in the future., Competing Interests: Declaration of interests P.L.J.d.K. is a co-founder and shareholder of Cleara Biotech BV, the Netherlands. D.A.P. works as a scientist at Cleara Biotech BV, the Netherlands., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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85. A doxycycline- and light-inducible Cre recombinase mouse model for optogenetic genome editing.
- Author
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Vizoso M, E J Pritchard C, Bombardelli L, van den Broek B, Krimpenfort P, Beijersbergen RL, Jalink K, and van Rheenen J
- Subjects
- Mice, Animals, Mice, Transgenic, Gene Editing, Integrases genetics, Integrases metabolism, Mice, Inbred Strains, Doxycycline pharmacology, Optogenetics
- Abstract
The experimental need to engineer the genome both in time and space, has led to the development of several photoactivatable Cre recombinase systems. However, the combination of inefficient and non-intentional background recombination has prevented thus far the wide application of these systems in biological and biomedical research. Here, we engineer an optimized photoactivatable Cre recombinase system that we refer to as doxycycline- and light-inducible Cre recombinase (DiLiCre). Following extensive characterization in cancer cell and organoid systems, we generate a DiLiCre mouse line, and illustrated the biological applicability of DiLiCre for light-induced mutagenesis in vivo and positional cell-tracing by intravital microscopy. These experiments illustrate how newly formed HrasV12 mutant cells follow an unnatural movement towards the interfollicular dermis. Together, we develop an efficient photoactivatable Cre recombinase mouse model and illustrate how this model is a powerful genome-editing tool for biological and biomedical research., (© 2022. The Author(s).)
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- 2022
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86. MYO10-filopodia support basement membranes at pre-invasive tumor boundaries.
- Author
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Peuhu E, Jacquemet G, Scheele CLGJ, Isomursu A, Laisne MC, Koskinen LM, Paatero I, Thol K, Georgiadou M, Guzmán C, Koskinen S, Laiho A, Elo LL, Boström P, Hartiala P, van Rheenen J, and Ivaska J
- Subjects
- Humans, Female, Pseudopodia metabolism, Myosins metabolism, Basement Membrane metabolism, Carcinoma, Intraductal, Noninfiltrating metabolism, Carcinoma, Intraductal, Noninfiltrating pathology, Breast Neoplasms pathology, Carcinoma, Ductal, Breast metabolism
- Abstract
Ductal carcinoma in situ (DCIS) is a pre-invasive stage of breast cancer. During invasion, the encapsulating DCIS basement membrane (BM) is compromised, and tumor cells invade the surrounding stroma. The mechanisms that regulate functional epithelial BMs in vivo are poorly understood. Myosin-X (MYO10) is a filopodia-inducing protein associated with metastasis and poor clinical outcome in invasive breast cancer (IBC). We identify elevated MYO10 expression in human DCIS and IBC, and this suggests links with disease progression. MYO10 promotes filopodia formation and cell invasion in vitro and cancer-cell dissemination from progressively invasive human DCIS xenografts. However, MYO10-depleted xenografts are more invasive. These lesions exhibit compromised BMs, poorly defined borders, and increased cancer-cell dispersal and EMT-marker-positive cells. In addition, cancer spheroids are dependent on MYO10-filopodia to generate a near-continuous extracellular matrix boundary. Thus, MYO10 is protective in early-stage breast cancer, correlating with tumor-limiting BMs, and pro-invasive at later stages, facilitating cancer-cell dissemination., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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87. Retrograde movements determine effective stem cell numbers in the intestine.
- Author
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Azkanaz M, Corominas-Murtra B, Ellenbroek SIJ, Bruens L, Webb AT, Laskaris D, Oost KC, Lafirenze SJA, Annusver K, Messal HA, Iqbal S, Flanagan DJ, Huels DJ, Rojas-Rodríguez F, Vizoso M, Kasper M, Sansom OJ, Snippert HJ, Liberali P, Simons BD, Katajisto P, Hannezo E, and van Rheenen J
- Subjects
- Animals, Intestinal Mucosa cytology, Intestine, Small cytology, Mice, Receptors, G-Protein-Coupled, Wnt Proteins, Cell Count, Cell Movement, Intestines cytology, Stem Cells cytology
- Abstract
The morphology and functionality of the epithelial lining differ along the intestinal tract, but tissue renewal at all sites is driven by stem cells at the base of crypts
1-3 . Whether stem cell numbers and behaviour vary at different sites is unknown. Here we show using intravital microscopy that, despite similarities in the number and distribution of proliferative cells with an Lgr5 signature in mice, small intestinal crypts contain twice as many effective stem cells as large intestinal crypts. We find that, although passively displaced by a conveyor-belt-like upward movement, small intestinal cells positioned away from the crypt base can function as long-term effective stem cells owing to Wnt-dependent retrograde cellular movement. By contrast, the near absence of retrograde movement in the large intestine restricts cell repositioning, leading to a reduction in effective stem cell number. Moreover, after suppression of the retrograde movement in the small intestine, the number of effective stem cells is reduced, and the rate of monoclonal conversion of crypts is accelerated. Together, these results show that the number of effective stem cells is determined by active retrograde movement, revealing a new channel of stem cell regulation that can be experimentally and pharmacologically manipulated., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
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88. Epithelial-to-Mesenchymal Transition Drives Invasiveness of Breast Cancer Brain Metastases.
- Author
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Margarido AS, Uceda-Castro R, Hahn K, de Bruijn R, Kester L, Hofland I, Lohuis J, Seinstra D, Broeks A, Jonkers J, Broekman MLD, Wesseling P, Vennin C, Vizoso M, and van Rheenen J
- Abstract
(1) Background: an increasing number of breast cancer patients develop lethal brain metastases (BM). The complete removal of these tumors by surgery becomes complicated when cells infiltrate into the brain parenchyma. However, little is known about the nature of these invading cells in breast cancer brain metastasis (BCBM). (2) Methods: we use intravital microscopy through a cranial window to study the behavior of invading cells in a mouse model of BCBM. (3) Results: we demonstrate that BCBM cells that escape from the metastatic mass and infiltrate into brain parenchyma undergo epithelial-to-mesenchymal transition (EMT). Moreover, cells undergoing EMT revert to an epithelial state when growing tumor masses in the brain. Lastly, through multiplex immunohistochemistry, we confirm the presence of these infiltrative cells in EMT in patient samples. (4) Conclusions: together, our data identify the critical role of EMT in the invasive behavior of BCBM, which warrants further consideration to target those cells when treating BCBM.
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- 2022
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89. Tissue architecture in tumor initiation and progression.
- Author
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Almagro J, Messal HA, Elosegui-Artola A, van Rheenen J, and Behrens A
- Subjects
- Cell Transformation, Neoplastic pathology, Humans, Stromal Cells pathology, Neoplasms genetics, Neoplasms pathology, Tumor Microenvironment
- Abstract
The 3D architecture of tissues bearing tumors impacts on the mechanical microenvironment of cancer, the accessibility of stromal cells, and the routes of invasion. A myriad of intrinsic and extrinsic forces exerted by the cancer cells, the host tissue, and the molecular and cellular microenvironment modulate the morphology of the tumor and its malignant potential through mechanical, biochemical, genetic, and epigenetic cues. Recent studies have investigated how tissue architecture influences cancer biology from tumor initiation and progression to distant metastatic seeding and response to therapy. With a focus on carcinoma, the most common type of cancer, this review discusses the latest discoveries on how tumor architecture is built and how tissue morphology affects the biology and progression of cancer cells., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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90. Dynamic Visualization of TGF-β/SMAD3 Transcriptional Responses in Single Living Cells.
- Author
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Marvin DL, You L, Bornes L, van Dinther M, Peters N, Dang H, Hakuno SK, Hornsveld M, Kranenburg O, van Rheenen J, Rohling JHT, Chien MP, Ten Dijke P, and Ritsma L
- Abstract
Transforming growth factor-β (TGF-β) signaling is tightly controlled in duration and intensity during embryonic development and in the adult to maintain tissue homeostasis. To visualize the TGF-β/SMAD3 signaling kinetics, we developed a dynamic TGF-β/SMAD3 transcriptional fluorescent reporter using multimerized SMAD3/4 binding elements driving the expression of a quickly folded and highly unstable GFP protein. We demonstrate the specificity and sensitivity of this reporter and its wide application to monitor dynamic TGF-β/SMAD3 transcriptional responses in both 2D and 3D systems in vitro, as well as in vivo, using live-cell and intravital imaging. Using this reporter in B16F10 cells, we observed single cell heterogeneity in response to TGF-β challenge, which can be categorized into early, late, and non-responders. Because of its broad application potential, this reporter allows for new discoveries into how TGF-β/SMAD3-dependent transcriptional dynamics are affected during multistep and reversible biological processes.
- Published
- 2022
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91. Liver Colonization by Colorectal Cancer Metastases Requires YAP-Controlled Plasticity at the Micrometastatic Stage.
- Author
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Heinz MC, Peters NA, Oost KC, Lindeboom RGH, van Voorthuijsen L, Fumagalli A, van der Net MC, de Medeiros G, Hageman JH, Verlaan-Klink I, Borel Rinkes IHM, Liberali P, Gloerich M, van Rheenen J, Vermeulen M, Kranenburg O, and Snippert HJG
- Subjects
- Animals, Humans, Mice, Neoplasm Micrometastasis pathology, Neoplastic Stem Cells pathology, Colorectal Neoplasms pathology, Liver Neoplasms metabolism
- Abstract
Micrometastases of colorectal cancer can remain dormant for years prior to the formation of actively growing, clinically detectable lesions (i.e., colonization). A better understanding of this step in the metastatic cascade could help improve metastasis prevention and treatment. Here we analyzed liver specimens of patients with colorectal cancer and monitored real-time metastasis formation in mouse livers using intravital microscopy to reveal that micrometastatic lesions are devoid of cancer stem cells (CSC). However, lesions that grow into overt metastases demonstrated appearance of de novo CSCs through cellular plasticity at a multicellular stage. Clonal outgrowth of patient-derived colorectal cancer organoids phenocopied the cellular and transcriptomic changes observed during in vivo metastasis formation. First, formation of mature CSCs occurred at a multicellular stage and promoted growth. Conversely, failure of immature CSCs to generate more differentiated cells arrested growth, implying that cellular heterogeneity is required for continuous growth. Second, early-stage YAP activity was required for the survival of organoid-forming cells. However, subsequent attenuation of early-stage YAP activity was essential to allow for the formation of cell type heterogeneity, while persistent YAP signaling locked micro-organoids in a cellularly homogenous and growth-stalled state. Analysis of metastasis formation in mouse livers using single-cell RNA sequencing confirmed the transient presence of early-stage YAP activity, followed by emergence of CSC and non-CSC phenotypes, irrespective of the initial phenotype of the metastatic cell of origin. Thus, establishment of cellular heterogeneity after an initial YAP-controlled outgrowth phase marks the transition to continuously growing macrometastases., Significance: Characterization of the cell type dynamics, composition, and transcriptome of early colorectal cancer liver metastases reveals that failure to establish cellular heterogeneity through YAP-controlled epithelial self-organization prohibits the outgrowth of micrometastases. See related commentary by LeBleu, p. 1870., (©2022 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2022
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92. Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments.
- Author
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Kester L, Seinstra D, van Rossum AGJ, Vennin C, Hoogstraat M, van der Velden D, Opdam M, van Werkhoven E, Hahn K, Nederlof I, Lips EH, Mandjes IAM, van Leeuwen-Stok AE, Canisius S, van Tinteren H, Imholz ALT, Portielje JEA, Bos MEMM, Bakker SD, Rutgers EJ, Horlings HM, Wesseling J, Voest EE, Wessels LFA, Kok M, Oosterkamp HM, van Oudenaarden A, Linn SC, and van Rheenen J
- Subjects
- Cellular Microenvironment, Endothelial Cells pathology, Female, Humans, Tumor Microenvironment genetics, Breast Neoplasms drug therapy, Breast Neoplasms therapy
- Abstract
Purpose: Extensive work in preclinical models has shown that microenvironmental cells influence many aspects of cancer cell behavior, including metastatic potential and their sensitivity to therapeutics. In the human setting, this behavior is mainly correlated with the presence of immune cells. Here, in addition to T cells, B cells, macrophages, and mast cells, we identified the relevance of nonimmune cell types for breast cancer survival and therapy benefit, including fibroblasts, myoepithelial cells, muscle cells, endothelial cells, and seven distinct epithelial cell types., Experimental Design: Using single-cell sequencing data, we generated reference profiles for all these cell types. We used these reference profiles in deconvolution algorithms to optimally detangle the cellular composition of more than 3,500 primary breast tumors of patients that were enrolled in the SCAN-B and MATADOR clinical trials, and for which bulk mRNA sequencing data were available., Results: This large data set enables us to identify and subsequently validate the cellular composition of microenvironments that distinguish differential survival and treatment benefit for different treatment regimens in patients with primary breast cancer. In addition to immune cells, we have identified that survival and therapy benefit are characterized by various contributions of distinct epithelial cell types., Conclusions: From our study, we conclude that differential survival and therapy benefit of patients with breast cancer are characterized by distinct microenvironments that include specific populations of immune and epithelial cells., (©2021 The Authors; Published by the American Association for Cancer Research.)
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- 2022
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93. A guideline for the clinical management of basal cell naevus syndrome (Gorlin-Goltz syndrome).
- Author
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Verkouteren BJA, Cosgun B, Reinders MGHC, Kessler PAWK, Vermeulen RJ, Klaassens M, Lambrechts S, van Rheenen JR, van Geel M, Vreeburg M, and Mosterd K
- Subjects
- Humans, Basal Cell Nevus Syndrome therapy
- Published
- 2022
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94. Longitudinal Intravital Microscopy Using a Mammary Imaging Window with Replaceable Lid.
- Author
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Mourao L, Ciwinska M, van Rheenen J, and Scheele CLGJ
- Subjects
- Animals, Homeostasis, Intravital Microscopy methods, Mammary Glands, Animal diagnostic imaging
- Abstract
The branched structure of the mammary gland is highly dynamic and undergoes several phases of growth and remodeling after birth. Intravital microscopy in combination with skin flap surgery or implantation of imaging windows has been used to study the dynamics of the healthy mammary gland at different developmental stages. Most mammary imaging technologies are limited to a time frame of hours to days, whereas the majority of mammary gland remodeling processes occur in time frames of days to weeks. To study mammary gland remodeling, methods that allow optical access to the tissue of interest for extended time frames are required. Here, an improved version of the titanium mammary imaging window with a replaceable lid (R.MIW) is described that allows high-resolution imaging of the mammary gland with a cellular resolution for up to several weeks. Importantly, the R.MIW provides tissue access over the entire duration of the intravital imaging experiment and could therefore be used for local tissue manipulation, labeling, drug administration, or image-guided microdissection. Taken together, the R.MIW enables high-resolution characterization of the cellular dynamics during mammary gland development, homeostasis, and disease.
- Published
- 2022
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95. GFAP splice variants fine-tune glioma cell invasion and tumour dynamics by modulating migration persistence.
- Author
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Uceda-Castro R, van Asperen JV, Vennin C, Sluijs JA, van Bodegraven EJ, Margarido AS, Robe PAJ, van Rheenen J, and Hol EM
- Subjects
- Animals, Brain Neoplasms metabolism, Cell Line, Tumor, Female, Glioma metabolism, Intravital Microscopy, Male, Mice, Inbred C57BL, Neoplasm Invasiveness, Protein Isoforms, Mice, Brain pathology, Brain Neoplasms pathology, Cell Movement, Glial Fibrillary Acidic Protein metabolism, Glioma pathology
- Abstract
Glioma is the most common form of malignant primary brain tumours in adults. Their highly invasive nature makes the disease incurable to date, emphasizing the importance of better understanding the mechanisms driving glioma invasion. Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that is characteristic for astrocyte- and neural stem cell-derived gliomas. Glioma malignancy is associated with changes in GFAP alternative splicing, as the canonical isoform GFAPα is downregulated in higher-grade tumours, leading to increased dominance of the GFAPδ isoform in the network. In this study, we used intravital imaging and an ex vivo brain slice invasion model. We show that the GFAPδ and GFAPα isoforms differentially regulate the tumour dynamics of glioma cells. Depletion of either isoform increases the migratory capacity of glioma cells. Remarkably, GFAPδ-depleted cells migrate randomly through the brain tissue, whereas GFAPα-depleted cells show a directionally persistent invasion into the brain parenchyma. This study shows that distinct compositions of the GFAPnetwork lead to specific migratory dynamics and behaviours of gliomas., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
96. Multiphoton intravital microscopy of rodents.
- Author
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Scheele CLGJ, Herrmann D, Yamashita E, Celso CL, Jenne CN, Oktay MH, Entenberg D, Friedl P, Weigert R, Meijboom FLB, Ishii M, Timpson P, and van Rheenen J
- Abstract
Tissues are heterogeneous with respect to cellular and non-cellular components and in the dynamic interactions between these elements. To study the behaviour and fate of individual cells in these complex tissues, intravital microscopy (IVM) techniques such as multiphoton microscopy have been developed to visualize intact and live tissues at cellular and subcellular resolution. IVM experiments have revealed unique insights into the dynamic interplay between different cell types and their local environment, and how this drives morphogenesis and homeostasis of tissues, inflammation and immune responses, and the development of various diseases. This Primer introduces researchers to IVM technologies, with a focus on multiphoton microscopy of rodents, and discusses challenges, solutions and practical tips on how to perform IVM. To illustrate the unique potential of IVM, several examples of results are highlighted. Finally, we discuss data reproducibility and how to handle big imaging data sets., Competing Interests: Competing interests P.T. receives reagents from Kadmon, InxMed (also consultant), Redx Pharma, Équilibre Biopharmaceuticals and Amplia Therapeutics. Under a licensing agreement between Amplia Therapeutics and Garvan Institute of Medical Research, D.H. and P.T. (consultant) are entitled to milestone payments. All other authors declare no competing interests.
- Published
- 2022
- Full Text
- View/download PDF
97. Generation of mixed murine organoids to model cellular interactions.
- Author
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Krotenberg Garcia A, van Rheenen J, and Suijkerbuijk SJE
- Subjects
- Animals, Cell Culture Techniques, Cells, Cultured, Mice, Cell Communication physiology, Organoids cytology, Tissue Culture Techniques methods
- Abstract
Cell competition is a mechanism of interaction that dictates cell selection based on differences in cellular fitness. We designed a protocol to generate mixed murine organoids and enteroid monolayers used to study such complex cellular interactions in a mammalian system. This protocol is dedicated to follow the behavior of different cell populations over time, using (time-lapse) microscopy or transcriptome/proteome analysis. For complete details on the use and execution of this protocol, please refer to Krotenberg Garcia et al. (2021)., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
98. Distinct contributions of partial and full EMT to breast cancer malignancy.
- Author
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Lüönd F, Sugiyama N, Bill R, Bornes L, Hager C, Tang F, Santacroce N, Beisel C, Ivanek R, Bürglin T, Tiede S, van Rheenen J, and Christofori G
- Subjects
- Animals, Antineoplastic Agents pharmacology, Apoptosis, Biomarkers, Tumor genetics, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms metabolism, Cell Movement, Cell Proliferation, Female, Humans, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms metabolism, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Invasiveness, Sequence Analysis, RNA, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Biomarkers, Tumor metabolism, Breast Neoplasms pathology, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Lung Neoplasms secondary
- Abstract
Epithelial-mesenchymal transition (EMT) is a transient, reversible process of cell de-differentiation where cancer cells transit between various stages of an EMT continuum, including epithelial, partial EMT, and mesenchymal cell states. We have employed Tamoxifen-inducible dual recombinase lineage tracing systems combined with live imaging and 5-cell RNA sequencing to track cancer cells undergoing partial or full EMT in the MMTV-PyMT mouse model of metastatic breast cancer. In primary tumors, cancer cells infrequently undergo EMT and mostly transition between epithelial and partial EMT states but rarely reach full EMT. Cells undergoing partial EMT contribute to lung metastasis and chemoresistance, whereas full EMT cells mostly retain a mesenchymal phenotype and fail to colonize the lungs. However, full EMT cancer cells are enriched in recurrent tumors upon chemotherapy. Hence, cancer cells in various stages of the EMT continuum differentially contribute to hallmarks of breast cancer malignancy, such as tumor invasion, metastasis, and chemoresistance., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
99. LGR6 marks nephron progenitor cells.
- Author
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van Ineveld RL, Margaritis T, Kooiman BAP, Groenveld F, Ariese HCR, Lijnzaad P, Johnson HR, Korving J, Wehrens EJ, Holstege F, van Rheenen J, Drost J, Rios AC, and Bos FL
- Subjects
- Cell Differentiation, Mesoderm, Organogenesis genetics, Nephrons, Stem Cells
- Abstract
Background: Nephron progenitor cells (NPCs) undergo a stepwise process to generate all mature nephron structures. Mesenchymal to epithelial transition (MET) is considered a multistep process of NPC differentiation to ensure progressive establishment of new nephrons. However, despite this important role, to date, no marker for NPCs undergoing MET in the nephron exists., Results: Here, we identify LGR6 as a NPC marker, expressed in very early cap mesenchyme, pre-tubular aggregates, renal vesicles, and in segments of S-shaped bodies, following the trajectory of MET. By using a lineage tracing approach in embryonic explants in combination with confocal imaging and single-cell RNA sequencing, we provide evidence for the multiple fates of LGR6+ cells during embryonic nephrogenesis. Moreover, by using long-term in vivo lineage tracing, we show that postnatal LGR6+ cells are capable of generating the multiple lineages of the nephrons., Conclusions: Given the profound early mesenchymal expression and MET signature of LGR6
+ cells, together with the lineage tracing of mesenchymal LGR6+ cells, we conclude that LGR6+ cells contribute to all nephrogenic segments by undergoing MET. LGR6+ cells can therefore be considered an early committed NPC population during embryonic and postnatal nephrogenesis with potential regenerative capability., (© 2021 The Authors. Developmental Dynamics published by Wiley Periodicals LLC on behalf of American Association of Anatomists.)- Published
- 2021
- Full Text
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100. Regulation of a progenitor gene program by SOX4 is essential for mammary tumor proliferation.
- Author
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Roukens MG, Frederiks CL, Seinstra D, Braccioli L, Khalil AA, Pals C, De Neck S, Bornes L, Beerling E, Mokry M, de Bruin A, Westendorp B, van Rheenen J, and Coffer PJ
- Subjects
- Animals, Breast Neoplasms genetics, CRISPR-Cas Systems, Cell Cycle Proteins genetics, Epithelial-Mesenchymal Transition, Female, Gene Expression Regulation, Neoplastic, Gene Silencing, Humans, Lung Neoplasms genetics, Mice, Neoplasm Transplantation, Organoids pathology, Breast Neoplasms pathology, Lung Neoplasms pathology, Lung Neoplasms secondary, Organoids transplantation, SOXC Transcription Factors genetics
- Abstract
In breast cancer the transcription factor SOX4 has been shown to be associated with poor survival, increased tumor size and metastasis formation. This has mostly been attributed to the ability of SOX4 to regulate Epithelial-to-Mesenchymal-Transition (EMT). However, SOX4 regulates target gene transcription in a context-dependent manner that is determined by the cellular and epigenetic state. In this study we have investigated the loss of SOX4 in mammary tumor development utilizing organoids derived from a PyMT genetic mouse model of breast cancer. Using CRISPR/Cas9 to abrogate SOX4 expression, we found that SOX4 is required for inhibiting differentiation by regulating a subset of genes that are highly activated in fetal mammary stem cells (fMaSC). In this way, SOX4 re-activates an oncogenic transcriptional program that is regulated in many progenitor cell-types during embryonic development. SOX4-knockout organoids are characterized by the presence of more differentiated cells that exhibit luminal or basal gene expression patterns, but lower expression of cell cycle genes. In agreement, primary tumor growth and metastatic outgrowth in the lungs are impaired in SOX4
KO tumors. Finally, SOX4KO tumors show a severe loss in competitive capacity to grow out compared to SOX4-proficient cells in primary tumors. Our study identifies a novel role for SOX4 in maintaining mammary tumors in an undifferentiated and proliferative state. Therapeutic manipulation of SOX4 function could provide a novel strategy for cancer differentiation therapy, which would promote differentiation and inhibit cycling of tumor cells., (© 2021. The Author(s).)- Published
- 2021
- Full Text
- View/download PDF
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