Publications

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7 Publications visible to you, out of a total of 7
MFmap: A semi-supervised generative model matching cell lines to tumours and cancer subtypes.

Abstract (Expand)

Translating in vitro results from experiments with cancer cell lines to clinical applications requires the selection of appropriate cell line models. Here we present MFmap (model fidelity map), a machine … learning model to simultaneously predict the cancer subtype of a cell line and its similarity to an individual tumour sample. The MFmap is a semi-supervised generative model, which compresses high dimensional gene expression, copy number variation and mutation data into cancer subtype informed low dimensional latent representations. The accuracy (test set F1 score >90%) of the MFmap subtype prediction is validated in ten different cancer datasets. We use breast cancer and glioblastoma cohorts as examples to show how subtype specific drug sensitivity can be translated to individual tumour samples. The low dimensional latent representations extracted by MFmap explain known and novel subtype specific features and enable the analysis of cell-state transformations between different subtypes. From a methodological perspective, we report that MFmap is a semi-supervised method which simultaneously achieves good generative and predictive performance and thus opens opportunities in other areas of computational biology.

Authors: X. Zhang, M. Kschischo

Date Published: 16th Dec 2021

Publication Type: Journal

Single-cell transcription profiles in Bloom syndrome patients link BLM deficiency with altered condensin complex expression signatures

Abstract (Expand)

Bloom syndrome (BS) is an autosomal recessive disease clinically characterized by primary microcephaly, growth deficiency, immunodeficiency, and predisposition to cancer. It is mainly caused by biallelic … loss-of-function mutations in the BLM gene, which encodes the BLM helicase, acting in DNA replication and repair processes. Here, we describe the gene expression profiles of three BS fibroblast cell lines harboring causative, biallelic truncating mutations obtained by single-cell (sc) transcriptome analysis. We compared the scRNA transcription profiles from three BS patient cell lines to two age-matched wild-type controls and observed specific deregulation of gene sets related to the molecular processes characteristically affected in BS, such as mitosis, chromosome segregation, cell cycle regulation, and genomic instability. We also found specific upregulation of genes of the Fanconi anemia pathway, in particular FANCM, FANCD2, and FANCI, which encode known interaction partners of BLM. The significant deregulation of genes associated with inherited forms of primary microcephaly observed in our study might explain in part the molecular pathogenesis of microcephaly in BS, one of the main clinical characteristics in patients. Finally, our data provide first evidence of a novel link between BLM dysfunction and transcriptional changes in condensin complex I and II genes. Overall, our study provides novel insights into gene expression profiles in BS on a single-cell level, linking specific genes and pathways to BLM dysfunction.

Authors: Ipek Ilgin Gönenc, Alexander Wolff, Markus Räschle, Bernd Wollnik

Date Published: 1st Oct 2021

Publication Type: Journal

Systems approaches identify the consequences of monosomy in somatic human cells.

Abstract (Expand)

Chromosome loss that results in monosomy is detrimental to viability, yet it is frequently observed in cancers. How cancers survive with monosomy is unknown. Using p53-deficient monosomic cell lines, … we find that chromosome loss impairs proliferation and genomic stability. Transcriptome and proteome analysis demonstrates reduced expression of genes encoded on the monosomes, which is partially compensated in some cases. Monosomy also induces global changes in gene expression. Pathway enrichment analysis reveals that genes involved in ribosome biogenesis and translation are downregulated in all monosomic cells analyzed. Consistently, monosomies display defects in protein synthesis and ribosome assembly. We further show that monosomies are incompatible with p53 expression, likely due to defects in ribosome biogenesis. Accordingly, impaired ribosome biogenesis and p53 inactivation are associated with monosomy in cancer. Our systematic study of monosomy in human cells explains why monosomy is so detrimental and reveals the importance of p53 for monosomy occurrence in cancer.

Authors: N. K. Chunduri, P. Menges, X. Zhang, A. Wieland, V. L. Gotsmann, B. R. Mardin, C. Buccitelli, J. O. Korbel, F. Willmund, M. Kschischo, M. Raeschle, Z. Storchova

Date Published: 22nd Sep 2021

Publication Type: Journal

The p53/p73 - p21(CIP1) tumor suppressor axis guards against chromosomal instability by restraining CDK1 in human cancer cells.

Abstract (Expand)

Whole chromosome instability (W-CIN) is a hallmark of human cancer and contributes to the evolvement of aneuploidy. W-CIN can be induced by abnormally increased microtubule plus end assembly rates … during mitosis leading to the generation of lagging chromosomes during anaphase as a major form of mitotic errors in human cancer cells. Here, we show that loss of the tumor suppressor genes TP53 and TP73 can trigger increased mitotic microtubule assembly rates, lagging chromosomes, and W-CIN. CDKN1A, encoding for the CDK inhibitor p21(CIP1), represents a critical target gene of p53/p73. Loss of p21(CIP1) unleashes CDK1 activity which causes W-CIN in otherwise chromosomally stable cancer cells. Consequently, induction of CDK1 is sufficient to induce abnormal microtubule assembly rates and W-CIN. Vice versa, partial inhibition of CDK1 activity in chromosomally unstable cancer cells corrects abnormal microtubule behavior and suppresses W-CIN. Thus, our study shows that the p53/p73 - p21(CIP1) tumor suppressor axis, whose loss is associated with W-CIN in human cancer, safeguards against chromosome missegregation and aneuploidy by preventing abnormally increased CDK1 activity.

Authors: A. K. Schmidt, K. Pudelko, J. E. Boekenkamp, K. Berger, M. Kschischo, H. Bastians

Date Published: 11th Nov 2020

Publication Type: Journal

Mild replication stress causes aneuploidy by deregulating microtubule dynamics in mitosis.

Abstract (Expand)

Chromosomal instability (CIN) causes structural and numerical chromosome aberrations and represents a hallmark of cancer. Replication stress (RS) has emerged as a driver for structural chromosome … aberrations while mitotic defects can cause whole chromosome missegregation and aneuploidy. Recently, first evidence indicated that RS can also influence chromosome segregation in cancer cells exhibiting CIN, but the underlying mechanisms remain unknown. Here, we show that chromosomally unstable cancer cells suffer from very mild RS, which allows efficient proliferation and which can be mimicked by treatment with very low concentrations of aphidicolin. Both, endogenous RS and aphidicolin-induced very mild RS cause chromosome missegregation during mitosis leading to the induction of aneuploidy. Moreover, RS triggers an increase in microtubule plus end growth rates in mitosis, an abnormality previously identified to cause chromosome missegregation in cancer cells. In fact, RS-induced chromosome missegregation is mediated by increased mitotic microtubule growth rates and is suppressed after restoration of proper microtubule growth rates and upon rescue of replication stress. Hence, very mild and cancer-relevant RS triggers aneuploidy by deregulating microtubule dynamics in mitosis.

Authors: N. Bohly, M. Kistner, H. Bastians

Date Published: 27th Aug 2019

Publication Type: Journal

Dormant replication origin firing links replication stress to whole chromosomal instability in human cancer

Abstract (Expand)

Chromosomal instability (CIN) is a hallmark of cancer and comprises structural CIN (S-CIN) and whole chromosome instability (W-CIN). Replication stress (RS), a condition of slowed or stalled DNA … replication during S phase, has been linked to S-CIN, whereas defects in mitosis leading to chromosome missegregation and aneuploidy can account for W-CIN. It is well established that RS can activate additional replication origin firing that is considered as a rescue mechanism to suppress chromosomal instability in the presence of RS. In contrast, we show here that an increase in replication origin firing during S phase can contribute to W-CIN in human cancer cells. Increased origin firing can be specifically triggered by overexpression of origin firing genes including GINS1 and CDC45, whose elevated expression significantly correlates with W-CIN in human cancer specimens. Moreover, endogenous mild RS present in cancer cells characterized by W-CIN or modulation of the origin firing regulating ATR-CDK1-RIF1 axis induces dormant origin firing, which is sufficient to trigger chromosome missegregation and W-CIN. Importantly, chromosome missegregation upon increased dormant origin firing is mediated by increased microtubule growth rates leading to the generation of lagging chromosomes in mitosis, a condition prevalent in chromosomally unstable cancer cells. Thus, our study identified increased or dormant replication origin firing as a hitherto unrecognized, but cancer-relevant trigger for chromosomal instability.

Author: Ann-Kathrin Schmidt, Nicolas Böhly, Xiaoxiao Zhang, Benjamin O. Slusarenko, Magdalena Hennecke, Maik Kschischo, Holger Bastians

Date Published: No date defined

Publication Type: Unpublished

Distinct and common features of numerical and structural chromosomal instability across different cancer types

Abstract (Expand)

A large proportion of tumours is characterised by numerical or structural chromosomal instability (CIN), defined as an increased rate of gaining or losing whole chromosomes (W-CIN) or of accumulating … structural aberrations (S-CIN). Both W-CIN and S-CIN are associated with tumourigenesis, cancer progression, treatment resistance and clinical outcome. Although W-CIN and S-CIN can co-occur, they are initiated by different molecular events. By analysing tumour genomic data from 33 cancer types, we show that the majority of tumours with high levels of W-CIN underwent whole genome doubling, whereas S-CIN levels are strongly associated with homologous recombination deficiency. Both CIN phenotypes are prognostic in several cancer types. Most drugs are less efficient in high CIN cell lines, we also report compounds and drugs which could specifically target W-CIN or S-CIN. By analysing associations between CIN and bio-molecular entities at pathway and gene expression levels, we complement gene signatures of CIN and report that the drug resistance gene \textit{CKS1B} is strongly associated with both W-CIN and S-CIN. Finally, we propose a potential copy number dependent mechanism to activate the \textit{PI3K} pathway in high CIN tumours.

Editor:

Date Published: No date defined

Publication Type: Journal

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