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Article ; Online: High-grade serous ovarian carcinoma organoids as models of chromosomal instability.

Vias, Maria / Morrill Gavarró, Lena / Sauer, Carolin M / Sanders, Deborah A / Piskorz, Anna M / Couturier, Dominique-Laurent / Ballereau, Stéphane / Hernando, Bárbara / Schneider, Michael P / Hall, James / Correia-Martins, Filipe / Markowetz, Florian / Macintyre, Geoff / Brenton, James D

eLife

2023 Volume 12

Abstract: High-grade serous ovarian carcinoma (HGSOC) is the most genomically complex cancer, characterized by ... ...

Abstract	High-grade serous ovarian carcinoma (HGSOC) is the most genomically complex cancer, characterized by ubiquitous
MeSH term(s)	Humans ; Female ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Mutation ; Genomics ; Chromosomal Instability ; Organoids
Language	English
Publishing date	2023-05-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.83867
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Article ; Online: Omentum-derived matrix enables the study of metastatic ovarian cancer and stromal cell functions in a physiologically relevant environment.

Neilson, Lisa J / Cartwright, Douglas / Risteli, Maija / Jokinen, Elina M / McGarry, Lynn / Sandvik, Toni / Nikolatou, Konstantina / Hodge, Kelly / Atkinson, Samuel / Vias, Maria / Kay, Emily J / Brenton, James D / Carlin, Leo M / Bryant, David M / Salo, Tuula / Zanivan, Sara

Matrix biology plus

2023 Volume 19-20, Page(s) 100136

Abstract: High-grade serous (HGS) ovarian cancer is the most lethal gynaecological disease in the world and metastases is a major cause. The omentum is the preferential metastatic site in HGS ovarian cancer patients ... ...

Abstract	High-grade serous (HGS) ovarian cancer is the most lethal gynaecological disease in the world and metastases is a major cause. The omentum is the preferential metastatic site in HGS ovarian cancer patients and
Language	English
Publishing date	2023-11-22
Publishing country	Netherlands
Document type	Journal Article
ISSN	2590-0285
ISSN (online)	2590-0285
DOI	10.1016/j.mbplus.2023.100136
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Article ; Online: Positional influence on cellular transcriptional identity revealed through spatially segmented single-cell transcriptomics.

Morse, David B / Michalowski, Aleksandra M / Ceribelli, Michele / De Jonghe, Joachim / Vias, Maria / Riley, Deanna / Davies-Hill, Theresa / Voss, Ty / Pittaluga, Stefania / Muus, Christoph / Liu, Jiamin / Boyle, Samantha / Weitz, David A / Brenton, James D / Buenrostro, Jason D / Knowles, Tuomas P J / Thomas, Craig J

Cell systems

2023 Volume 14, Issue 6, Page(s) 464–481.e7

Abstract: Single-cell RNA sequencing (scRNA-seq) is a powerful technique for describing cell states. Identifying the spatial arrangement of these states in tissues remains challenging, with the existing methods requiring niche methodologies and expertise. Here, we ...

Abstract	Single-cell RNA sequencing (scRNA-seq) is a powerful technique for describing cell states. Identifying the spatial arrangement of these states in tissues remains challenging, with the existing methods requiring niche methodologies and expertise. Here, we describe segmentation by exogenous perfusion (SEEP), a rapid and integrated method to link surface proximity and environment accessibility to transcriptional identity within three-dimensional (3D) disease models. The method utilizes the steady-state diffusion kinetics of a fluorescent dye to establish a gradient along the radial axis of disease models. Classification of sample layers based on dye accessibility enables dissociated and sorted cells to be characterized by transcriptomic and regional identities. Using SEEP, we analyze spheroid, organoid, and in vivo tumor models of high-grade serous ovarian cancer (HGSOC). The results validate long-standing beliefs about the relationship between cell state and position while revealing new concepts regarding how spatially unique microenvironments influence the identity of individual cells within tumors.
MeSH term(s)	Transcriptome/genetics ; Gene Expression Profiling ; Kinetics ; Organoids ; Physics
Language	English
Publishing date	2023-06-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2854138-8
ISSN	2405-4720 ; 2405-4712
ISSN (online)	2405-4720
ISSN	2405-4712
DOI	10.1016/j.cels.2023.05.003
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Article ; Online: Longitudinal monitoring of disease burden and response using ctDNA from dried blood spots in xenograft models.

Sauer, Carolin M / Heider, Katrin / Belic, Jelena / Boyle, Samantha E / Hall, James A / Couturier, Dominique-Laurent / An, Angela / Vijayaraghavan, Aadhitthya / Reinius, Marika Av / Hosking, Karen / Vias, Maria / Rosenfeld, Nitzan / Brenton, James D

EMBO molecular medicine

2022 Volume 14, Issue 8, Page(s) e15729

Abstract: Whole-genome sequencing (WGS) of circulating tumour DNA (ctDNA) is now a clinically important biomarker for predicting therapy response, disease burden and disease progression. However, the translation of ctDNA monitoring into vital preclinical PDX ... ...

Abstract	Whole-genome sequencing (WGS) of circulating tumour DNA (ctDNA) is now a clinically important biomarker for predicting therapy response, disease burden and disease progression. However, the translation of ctDNA monitoring into vital preclinical PDX models has not been possible owing to low circulating blood volumes in small rodents. Here, we describe the longitudinal detection and monitoring of ctDNA from minute volumes of blood in PDX mice. We developed a xenograft Tumour Fraction (xTF) metric using shallow WGS of dried blood spots (DBS), and demonstrate its application to quantify disease burden, monitor treatment response and predict disease outcome in a preclinical study of PDX mice. Further, we show how our DBS-based ctDNA assay can be used to detect gene-specific copy number changes and examine the copy number landscape over time. Use of sequential DBS ctDNA assays could transform future trial designs in both mice and patients by enabling increased sampling and molecular monitoring.
MeSH term(s)	Animals ; Biomarkers, Tumor ; Circulating Tumor DNA/genetics ; Cost of Illness ; Heterografts ; Mice ; Neoplasms/genetics ; Neoplasms/therapy
Chemical Substances	Biomarkers, Tumor ; Circulating Tumor DNA
Language	English
Publishing date	2022-06-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2467145-9
ISSN	1757-4684 ; 1757-4676
ISSN (online)	1757-4684
ISSN	1757-4676
DOI	10.15252/emmm.202215729
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Article ; Online: Molecular landscape and functional characterization of centrosome amplification in ovarian cancer.

Nature communications

2023 Volume 14, Issue 1, Page(s) 6505

Abstract: High-grade serous ovarian carcinoma (HGSOC) is characterised by poor outcome and extreme chromosome instability (CIN). Therapies targeting centrosome amplification (CA), a key mediator of chromosome missegregation, may have significant clinical utility ... ...

Abstract	High-grade serous ovarian carcinoma (HGSOC) is characterised by poor outcome and extreme chromosome instability (CIN). Therapies targeting centrosome amplification (CA), a key mediator of chromosome missegregation, may have significant clinical utility in HGSOC. However, the prevalence of CA in HGSOC, its relationship to genomic biomarkers of CIN and its potential impact on therapeutic response have not been defined. Using high-throughput multi-regional microscopy on 287 clinical HGSOC tissues and 73 cell lines models, here we show that CA through centriole overduplication is a highly recurrent and heterogeneous feature of HGSOC and strongly associated with CIN and genome subclonality. Cell-based studies showed that high-prevalence CA is phenocopied in ovarian cancer cell lines, and that high CA is associated with increased multi-treatment resistance; most notably to paclitaxel, the commonest treatment used in HGSOC. CA in HGSOC may therefore present a potential driver of tumour evolution and a powerful biomarker for response to standard-of-care treatment.
MeSH term(s)	Humans ; Female ; Ovarian Neoplasms/pathology ; Paclitaxel/pharmacology ; Paclitaxel/therapeutic use ; Centrosome/metabolism ; Cystadenocarcinoma, Serous/genetics
Chemical Substances	Paclitaxel (P88XT4IS4D)
Language	English
Publishing date	2023-10-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-41840-3
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Article: Terminal and progenitor lineage-survival oncogenes as cancer markers.

Vias, Maria / Ramos-Montoya, Antonio / Mills, Ian G

Trends in molecular medicine

2008 Volume 14, Issue 11, Page(s) 486–494

Abstract: Tumour classification has traditionally focused on differentiation and cellular morphology, and latterly on the application of genomic approaches. By combining chromatin immunoprecipitation with expression array, it has been possible to identify direct ... ...

Abstract	Tumour classification has traditionally focused on differentiation and cellular morphology, and latterly on the application of genomic approaches. By combining chromatin immunoprecipitation with expression array, it has been possible to identify direct gene targets for transcription factors for nuclear hormone receptors. At the same time, there have been great strides in deriving stem and progenitor cells from tissues. It is therefore timely to propose that pairing the isolation of these cell subpopulations from tissues and tumours with these genomics approaches will reveal conserved gene targets for transcription factors. By focusing on transcription factors (lineage-survival oncogenes) with roles in both organogenesis and tumourigenesis at multiple organ sites, we suggest that this comparative genomics approach will enable developmental biology to be used more fully in relation to understanding tumour progression and will reveal new cancer markers. We focus here on neurogenesis and neuroendocrine differentiation in tumours.
MeSH term(s)	Animals ; Biomarkers, Tumor/metabolism ; Cell Lineage ; Chromatin Immunoprecipitation ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Neoplasms/metabolism ; Neoplasms/physiopathology ; Neoplasms/therapy ; Oligonucleotide Array Sequence Analysis ; Oncogenes ; Signal Transduction ; Stem Cells/cytology ; Stem Cells/metabolism
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2008-10-15
Publishing country	England
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2036490-8
ISSN	1471-499X ; 1471-4914
ISSN (online)	1471-499X
ISSN	1471-4914
DOI	10.1016/j.molmed.2008.09.002
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Zs.A 4345: Show issues

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Article ; Online: Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer.

Martins, Filipe Correia / Couturier, Dominique-Laurent / de Santiago, Ines / Sauer, Carolin Margarethe / Vias, Maria / Angelova, Mihaela / Sanders, Deborah / Piskorz, Anna / Hall, James / Hosking, Karen / Amirthanayagam, Anumithra / Cosulich, Sabina / Carnevalli, Larissa / Davies, Barry / Watkins, Thomas B K / Funingana, Ionut G / Bolton, Helen / Haldar, Krishnayan / Latimer, John /

Baldwin, Peter / Crawford, Robin / Eldridge, Matthew / Basu, Bristi / Jimenez-Linan, Mercedes / Mcpherson, Andrew W / McGranahan, Nicholas / Litchfield, Kevin / Shah, Sohrab P / McNeish, Iain / Caldas, Carlos / Evan, Gerard / Swanton, Charles / Brenton, James D

Nature communications

2022 Volume 13, Issue 1, Page(s) 6360

Abstract: Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma (HGSOC). Here we show that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes ... ...

Abstract	Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma (HGSOC). Here we show that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression and methylation status. We identify five prevalent clonal driver SCNAs (chromosomal amplifications encompassing MYC, PIK3CA, CCNE1, KRAS and TERT) from multi-regional HGSOC data and reason that their strong selection should prioritise them as key biomarkers for targeted therapies. We use primary HGSOC spheroid models to test interactions between in vitro targeted therapy and SCNAs. MYC chromosomal copy number is associated with in-vitro and clinical response to paclitaxel and in-vitro response to mTORC1/2 inhibition. Activation of the mTOR survival pathway in the context of MYC-amplified HGSOC is statistically associated with increased prevalence of SCNAs in genes from the PI3K pathway. Co-occurrence of amplifications in MYC and genes from the PI3K pathway is independently observed in squamous lung cancer and triple negative breast cancer. In this work, we show that identifying co-occurrence of clonal driver SCNA genes could be used to tailor therapeutics for precision medicine.
MeSH term(s)	Humans ; Female ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; DNA Copy Number Variations ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics ; Cystadenocarcinoma, Serous/drug therapy ; Cystadenocarcinoma, Serous/genetics ; Cystadenocarcinoma, Serous/metabolism ; Class I Phosphatidylinositol 3-Kinases/genetics ; Class I Phosphatidylinositol 3-Kinases/metabolism ; Paclitaxel/therapeutic use ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/metabolism ; Mechanistic Target of Rapamycin Complex 1/metabolism
Chemical Substances	Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; Paclitaxel (P88XT4IS4D) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
Language	English
Publishing date	2022-10-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-33870-0
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Article: A role for neurotensin in bicalutamide resistant prostate cancer cells.

Vias, Maria / Burtt, Glyn / Culig, Zoran / Veerakumarasivam, Abhi / Neal, David E / Mills, Ian G

The Prostate

2006 Volume 67, Issue 2, Page(s) 190–202

Abstract: Background: Anti-androgens are administered as a principal treatment for prostate cancer. Aggressive hormone refractory disease is characterized in some cases by the development of a neuroendocrine phenotype. However little attention has been paid to ... ...

Abstract	Background: Anti-androgens are administered as a principal treatment for prostate cancer. Aggressive hormone refractory disease is characterized in some cases by the development of a neuroendocrine phenotype. However little attention has been paid to resistance pathways selected for by long-term treatment with non-steroidal anti-androgens. Methods: Using a resistant sub-line, LNCaP-Bic, we performed a comparative gene expression profiling using cDNA microarrays and target validation by qRT-PCR. Targets were then explored using cell proliferation, cell cycle analysis and in vitro invasion assays using siRNA technology. Results: Neurotensin/Neuromedin N (NTS) was upregulated in the LNCaP-Bic line at both the transcript and protein level. The resistant line was found to have an increased proliferation rate, more rapid cell cycle progression and increased invasiveness through Matrigel. Each phenotypic difference could be reduced using siRNA knockdown of NT. Conclusion: Increased expression of NT in bicalutamide resistant prostate cancer cells induces cell proliferation and invasion suggesting that this peptide may contribute to the development of bicalutamide resistant prostate cancer.
MeSH term(s)	Androgen Antagonists/pharmacology ; Anilides/pharmacology ; Cell Cycle ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Drug Resistance, Neoplasm ; Gene Expression Profiling ; Humans ; Male ; Microsatellite Repeats ; Neurotensin/genetics ; Neurotensin/metabolism ; Nitriles ; Oligonucleotide Array Sequence Analysis ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; RNA, Small Interfering/pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Tosyl Compounds ; Up-Regulation
Chemical Substances	Androgen Antagonists ; Anilides ; Nitriles ; RNA, Small Interfering ; Tosyl Compounds ; Neurotensin (39379-15-2) ; bicalutamide (A0Z3NAU9DP)
Language	English
Publishing date	2006-10-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604707-5
ISSN	1097-0045 ; 0270-4137
ISSN (online)	1097-0045
ISSN	0270-4137
DOI	10.1002/pros.20518
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Article ; Online: Microarray segmentation methods significantly influence data precision.

Ahmed, Ahmed Ashour / Vias, Maria / Iyer, N Gopalakrishna / Caldas, Carlos / Brenton, James D

Nucleic acids research

2004 Volume 32, Issue 5, Page(s) e50

Abstract: Little consideration has been given to the effect of different segmentation methods on the variability of data derived from microarray images. Previous work has suggested that the significant source of variability from microarray image analysis is from ... ...

Abstract	Little consideration has been given to the effect of different segmentation methods on the variability of data derived from microarray images. Previous work has suggested that the significant source of variability from microarray image analysis is from estimation of local background. In this study, we used Analysis of Variance (ANOVA) models to investigate the effect of methods of segmentation on the precision of measurements obtained from replicate microarray experiments. We used four different methods of spot segmentation (adaptive, fixed circle, histogram and GenePix) to analyse a total number of 156 172 spots from 12 microarray experiments. Using a two-way ANOVA model and the coefficient of repeatability, we show that the method of segmentation significantly affects the precision of the microarray data. The histogram method gave the lowest variability across replicate spots compared to other methods, and had the lowest pixel-to-pixel variability within spots. This effect on precision was independent of background subtraction. We show that these findings have direct, practical implications as the variability in precision between the four methods resulted in different numbers of genes being identified as differentially expressed. Segmentation method is an important source of variability in microarray data that directly affects precision and the identification of differentially expressed genes.
MeSH term(s)	Algorithms ; Analysis of Variance ; Cell Line ; DNA, Complementary ; Fluorescent Dyes ; Gene Expression Profiling/methods ; Humans ; Oligonucleotide Array Sequence Analysis/methods ; Reproducibility of Results
Chemical Substances	DNA, Complementary ; Fluorescent Dyes
Language	English
Publishing date	2004-03-17
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205588-5
ISSN	1362-4962 ; 1746-8272 ; 0305-1048 ; 0261-3166
ISSN (online)	1362-4962 ; 1746-8272
ISSN	0305-1048 ; 0261-3166
DOI	10.1093/nar/gnh047
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Article ; Online: Pro-neural transcription factors as cancer markers.

Vias, Maria / Massie, Charlie E / East, Philip / Scott, Helen / Warren, Anne / Zhou, Zongxiang / Nikitin, Alexander Yu / Neal, David E / Mills, Ian G

BMC medical genomics

2008 Volume 1, Page(s) 17

Abstract: Background: The aberrant transcription in cancer of genes normally associated with embryonic tissue differentiation at various organ sites may be a hallmark of tumour progression. For example, neuroendocrine differentiation is found more commonly in ... ...

Abstract	Background: The aberrant transcription in cancer of genes normally associated with embryonic tissue differentiation at various organ sites may be a hallmark of tumour progression. For example, neuroendocrine differentiation is found more commonly in cancers destined to progress, including prostate and lung. We sought to identify proteins which are involved in neuroendocrine differentiation and differentially expressed in aggressive/metastatic tumours. Results: Expression arrays were used to identify up-regulated transcripts in a neuroendocrine (NE) transgenic mouse model of prostate cancer. Amongst these were several genes normally expressed in neural tissues, including the pro-neural transcription factors Ascl1 and Hes6. Using quantitative RT-PCR and immuno-histochemistry we showed that these same genes were highly expressed in castrate resistant, metastatic LNCaP cell-lines. Finally we performed a meta-analysis on expression array datasets from human clinical material. The expression of these pro-neural transcripts effectively segregates metastatic from localised prostate cancer and benign tissue as well as sub-clustering a variety of other human cancers. Conclusion: By focussing on transcription factors known to drive normal tissue development and comparing expression signatures for normal and malignant mouse tissues we have identified two transcription factors, Ascl1 and Hes6, which appear effective markers for an aggressive phenotype in all prostate models and tissues examined. We suggest that the aberrant initiation of differentiation programs may confer a selective advantage on cells in all contexts and this approach to identify biomarkers therefore has the potential to uncover proteins equally applicable to pre-clinical and clinical cancer biology.
Language	English
Publishing date	2008-05-19
Publishing country	England
Document type	Journal Article
ISSN	1755-8794
ISSN (online)	1755-8794
DOI	10.1186/1755-8794-1-17
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