Yi Bei

All Publications

• Spatial single-cell omics in liver studies: cautions on metanarrative pitfalls. Gut Liu, H., Bei, Y., Shao, Z., Berger, H., Guillot, A. 2025

  View details for DOI 10.1136/gutjnl-2025-337322

  View details for PubMedID 41198174

• Elimusertib has Antitumor Activity in Preclinical Patient-Derived Pediatric Solid Tumor Models MOLECULAR CANCER THERAPEUTICS Pusch, F. F., Garcia, H., Xu, R., Guergen, D., Bei, Y., Brueckner, L., Roeefzaad, C., von Stebut, J., Bardinet, V., Gonzalez, R., Eggert, A., Schulte, J. H., Hundsdoerfer, P., Seifert, G., Haase, K., Schaefer, B. W., Wachtel, M., Kuehl, A. A., Ortiz, M. V., Wengner, A. M., Scheer, M., Henssen, A. G. 2024; 23 (4): 507-519

  Abstract

  The small-molecule inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), elimusertib, is currently being tested clinically in various cancer entities in adults and children. Its preclinical antitumor activity in pediatric malignancies, however, is largely unknown. We here assessed the preclinical activity of elimusertib in 38 cell lines and 32 patient-derived xenograft (PDX) models derived from common pediatric solid tumor entities. Detailed in vitro and in vivo molecular characterization of the treated models enabled the evaluation of response biomarkers. Pronounced objective response rates were observed for elimusertib monotherapy in PDX, when treated with a regimen currently used in clinical trials. Strikingly, elimusertib showed stronger antitumor effects than some standard-of-care chemotherapies, particularly in alveolar rhabdomysarcoma PDX. Thus, elimusertib has strong preclinical antitumor activity in pediatric solid tumor models, which may translate to clinically meaningful responses in patients.

  View details for DOI 10.1158/1535-7163.MCT-23-0094

  View details for Web of Science ID 001195461000010

  View details for PubMedID 38159110

  View details for PubMedCentralID PMC10985474

• Passenger Gene Coamplifications Create Collateral Therapeutic Vulnerabilities in Cancer CANCER DISCOVERY Bei, Y., Brame, L., Kirchner, M., Fritsche-Guenther, R., Kunz, S., Bhattacharya, A., Rusu, M., Guergen, D., Dubios, F. P. B., Koeppke, J. K. C., Proba, J., Wittstruck, N., Sidorova, O., Gonzalez, R., Garcia, H., Brueckner, L., Xu, R., Giurgiu, M., Rodriguez-Fos, E., Yu, Q., Spanjaard, B., Koche, R. P., Schmitt, C. A., Schulte, J. H., Eggert, A., Haase, K., Kirwan, J., Hagemann, A. I. H., Mertins, P., Doerr, J. R., Henssen, A. G. 2024; 14 (3): 492-507

  Abstract

  DNA amplifications in cancer do not only harbor oncogenes. We sought to determine whether passenger coamplifications could create collateral therapeutic vulnerabilities. Through an analysis of >3,000 cancer genomes followed by the interrogation of CRISPR-Cas9 loss-of-function screens across >700 cancer cell lines, we determined that passenger coamplifications are accompanied by distinct dependency profiles. In a proof-of-principle study, we demonstrate that the coamplification of the bona fide passenger gene DEAD-Box Helicase 1 (DDX1) creates an increased dependency on the mTOR pathway. Interaction proteomics identified tricarboxylic acid (TCA) cycle components as previously unrecognized DDX1 interaction partners. Live-cell metabolomics highlighted that this interaction could impair TCA activity, which in turn resulted in enhanced mTORC1 activity. Consequently, genetic and pharmacologic disruption of mTORC1 resulted in pronounced cell death in vitro and in vivo. Thus, structurally linked coamplification of a passenger gene and an oncogene can result in collateral vulnerabilities.We demonstrate that coamplification of passenger genes, which were largely neglected in cancer biology in the past, can create distinct cancer dependencies. Because passenger coamplifications are frequent in cancer, this principle has the potential to expand target discovery in oncology. This article is featured in Selected Articles from This Issue, p. 384.

  View details for DOI 10.1158/2159-8290.CD-23-1189

  View details for Web of Science ID 001178768700004

  View details for PubMedID 38197697

  View details for PubMedCentralID PMC10911929

• Parallel sequencing of extrachromosomal circular DNAs and transcriptomes in single cancer cells. Nature genetics Chamorro González, R., Conrad, T., Stöber, M. C., Xu, R., Giurgiu, M., Rodriguez-Fos, E., Kasack, K., Brückner, L., van Leen, E., Helmsauer, K., Dorado Garcia, H., Stefanova, M. E., Hung, K. L., Bei, Y., Schmelz, K., Lodrini, M., Mundlos, S., Chang, H. Y., Deubzer, H. E., Sauer, S., Eggert, A., Schulte, J. H., Schwarz, R. F., Haase, K., Koche, R. P., Henssen, A. G. 2023

  Abstract

  Extrachromosomal DNAs (ecDNAs) are common in cancer, but many questions about their origin, structural dynamics and impact on intratumor heterogeneity are still unresolved. Here we describe single-cell extrachromosomal circular DNA and transcriptome sequencing (scEC&T-seq), a method for parallel sequencing of circular DNAs and full-length mRNA from single cells. By applying scEC&T-seq to cancer cells, we describe intercellular differences in ecDNA content while investigating their structural heterogeneity and transcriptional impact. Oncogene-containing ecDNAs were clonally present in cancer cells and drove intercellular oncogene expression differences. In contrast, other small circular DNAs were exclusive to individual cells, indicating differences in their selection and propagation. Intercellular differences in ecDNA structure pointed to circular recombination as a mechanism of ecDNA evolution. These results demonstrate scEC&T-seq as an approach to systematically characterize both small and large circular DNA in cancer cells, which will facilitate the analysis of these DNA elements in cancer and beyond.

  View details for DOI 10.1038/s41588-023-01386-y

  View details for PubMedID 37142849

  View details for PubMedCentralID 5334176

• Therapeutic targeting of ATR in alveolar rhabdomyosarcoma NATURE COMMUNICATIONS Garcia, H., Pusch, F., Bei, Y., von Stebut, J., Ibanez, G., Guillan, K., Imami, K., Guergen, D., Rolff, J., Helmsauer, K., Meyer-Liesener, S., Timme, N., Bardinet, V., Gonzalez, R., MacArthur, I. C., Chen, C. Y., Schulz, J., Wengner, A. M., Furth, C., Lala, B., Eggert, A., Seifert, G., Hundsoerfer, P., Kirchner, M., Mertins, P., Selbach, M., Lissat, A., Dubois, F., Horst, D., Schulte, J. H., Spuler, S., You, D., Dela Cruz, F., Kung, A. L., Haase, K., DiVirgilio, M., Scheer, M., Ortiz, M. V., Henssen, A. G. 2022; 13 (1): 4297

  Abstract

  Despite advances in multi-modal treatment approaches, clinical outcomes of patients suffering from PAX3-FOXO1 fusion oncogene-expressing alveolar rhabdomyosarcoma (ARMS) remain dismal. Here we show that PAX3-FOXO1-expressing ARMS cells are sensitive to pharmacological ataxia telangiectasia and Rad3 related protein (ATR) inhibition. Expression of PAX3-FOXO1 in muscle progenitor cells is not only sufficient to increase sensitivity to ATR inhibition, but PAX3-FOXO1-expressing rhabdomyosarcoma cells also exhibit increased sensitivity to structurally diverse inhibitors of ATR. Mechanistically, ATR inhibition leads to replication stress exacerbation, decreased BRCA1 phosphorylation and reduced homologous recombination-mediated DNA repair pathway activity. Consequently, ATR inhibitor treatment increases sensitivity of ARMS cells to PARP1 inhibition in vitro, and combined treatment with ATR and PARP1 inhibitors induces complete regression of primary patient-derived ARMS xenografts in vivo. Lastly, a genome-wide CRISPR activation screen (CRISPRa) in combination with transcriptional analyses of ATR inhibitor resistant ARMS cells identifies the RAS-MAPK pathway and its targets, the FOS gene family, as inducers of resistance to ATR inhibition. Our findings provide a rationale for upcoming biomarker-driven clinical trials of ATR inhibitors in patients suffering from ARMS.

  View details for DOI 10.1038/s41467-022-32023-7

  View details for Web of Science ID 001029817200001

  View details for PubMedID 35879366

  View details for PubMedCentralID PMC9314382

• Enhancer hijacking determines extrachromosomal circular <i>MYCN</i> amplicon architecture in neuroblastoma NATURE COMMUNICATIONS Helmsauer, K., Valieva, M. E., Ali, S., Gonzalez, R., Schoepflin, R., Roeefzaad, C., Bei, Y., Garcia, H., Rodriguez-Fos, E., Puiggros, M., Kasack, K., Haase, K., Keskeny, C., Chen, C. Y., Kuschel, L. P., Euskirchen, P., Heinrich, V., Robson, M., Rosswog, C., Toedling, J., Szymansky, A., Hertwig, F., Fischer, M., Torrents, D., Eggert, A., Schulte, J. H., Mundlos, S., Henssen, A. G., Koche, R. P. 2020; 11 (1): 5823

  Abstract

  MYCN amplification drives one in six cases of neuroblastoma. The supernumerary gene copies are commonly found on highly rearranged, extrachromosomal circular DNA (ecDNA). The exact amplicon structure has not been described thus far and the functional relevance of its rearrangements is unknown. Here, we analyze the MYCN amplicon structure using short-read and Nanopore sequencing and its chromatin landscape using ChIP-seq, ATAC-seq and Hi-C. This reveals two distinct classes of amplicons which explain the regulatory requirements for MYCN overexpression. The first class always co-amplifies a proximal enhancer driven by the noradrenergic core regulatory circuit (CRC). The second class of MYCN amplicons is characterized by high structural complexity, lacks key local enhancers, and instead contains distal chromosomal fragments harboring CRC-driven enhancers. Thus, ectopic enhancer hijacking can compensate for the loss of local gene regulatory elements and explains a large component of the structural diversity observed in MYCN amplification.

  View details for DOI 10.1038/s41467-020-19452-y

  View details for Web of Science ID 000594725700029

  View details for PubMedID 33199677

  View details for PubMedCentralID PMC7669906

• Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma (vol 52, pg 29, 2019) NATURE GENETICS Koche, R. P., Rodriguez-Fos, E., Helmsauer, K., Burkert, M., MacArthur, I. C., Maag, J., Chamorro, R., Munoz-Perez, N., Puiggros, M., Garcia, H., Bei, Y., Roeefzaad, C., Bardinet, V., Szymansky, A., Winkler, A., Thole, T., Timme, N., Kasack, K., Fuchs, S., Klironomos, F., Thiessen, N., Blanc, E., Schmelz, K., Kuenkele, A., Hundsdoerfer, P., Rosswog, C., Theissen, J., Beule, D., Deubzer, H., Sauer, S., Toedling, J., Fischer, M., Hertwig, F., Schwarz, R. F., Eggert, A., Torrents, D., Schulte, J. H., Henssen, A. G. 2020; 52 (4): 464

  Abstract

  An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  View details for DOI 10.1038/s41588-020-0598-1

  View details for Web of Science ID 000516890000002

  View details for PubMedID 32107479

• Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors TRANSLATIONAL ONCOLOGY Timme, N., Han, Y., Liu, S., Yosief, H. O., Garcia, H., Bei, Y., Klironomos, F., MacArthur, I. C., Szymansky, A., von Stebut, J., Bardinet, V., Dohna, C., Kuenkele, A., Rolff, J., Hundsdoerfer, P., Lissat, A., Seifert, G., Eggert, A., Schulte, J. H., Zhang, W., Henssen, A. G. 2020; 13 (2): 221-232

  Abstract

  Simultaneous inhibition of multiple molecular targets is an established strategy to improve the continuance of clinical response to therapy. Here, we screened 49 molecules with dual nanomolar inhibitory activity against BRD4 and PLK1, best classified as dual kinase-bromodomain inhibitors, in pediatric tumor cell lines for their antitumor activity. We identified two candidate dual kinase-bromodomain inhibitors with strong and tumor-specific activity against neuroblastoma, medulloblastoma, and rhabdomyosarcoma tumor cells. Dual PLK1 and BRD4 inhibitor treatment suppressed proliferation and induced apoptosis in pediatric tumor cell lines at low nanomolar concentrations. This was associated with reduced MYCN-driven gene expression as assessed by RNA sequencing. Treatment of patient-derived xenografts with dual inhibitor UMB103 led to significant tumor regression. We demonstrate that concurrent inhibition of two central regulators of MYC protein family of protooncogenes, BRD4, and PLK1, with single small molecules has strong and specific antitumor effects in preclinical pediatric cancer models.

  View details for DOI 10.1016/j.tranon.2019.09.013

  View details for Web of Science ID 000513932000011

  View details for PubMedID 31869746

  View details for PubMedCentralID PMC6931204

• Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma NATURE GENETICS Koche, R. P., Rodriguez-Fos, E., Helmsauer, K., Burkert, M., MacArthur, I. C., Maag, J., Chamorro, R., Munoz-Perez, N., Puiggros, M., Dorado Garcia, H., Bei, Y., Roeefzaad, C., Bardinet, V., Szymansky, A., Winkler, A., Thole, T., Timme, N., Kasack, K., Fuchs, S., Klironomos, F., Thiessen, N., Blanc, E., Schmelz, K., Kuenkele, A., Hundsdoerfer, P., Rosswog, C., Theissen, J., Beule, D., Deubzer, H., Sauer, S., Toedling, J., Fischer, M., Hertwig, F., Schwarz, R. F., Eggert, A., Torrents, D., Schulte, J. H., Henssen, A. G. 2020; 52 (1): 29-+

  Abstract

  Extrachromosomal circularization of DNA is an important genomic feature in cancer. However, the structure, composition and genome-wide frequency of extrachromosomal circular DNA have not yet been profiled extensively. Here, we combine genomic and transcriptomic approaches to describe the landscape of extrachromosomal circular DNA in neuroblastoma, a tumor arising in childhood from primitive cells of the sympathetic nervous system. Our analysis identifies and characterizes a wide catalog of somatically acquired and undescribed extrachromosomal circular DNAs. Moreover, we find that extrachromosomal circular DNAs are an unanticipated major source of somatic rearrangements, contributing to oncogenic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome. Cancer-causing lesions can emerge out of circle-derived rearrangements and are associated with adverse clinical outcome. It is highly probable that circle-derived rearrangements represent an ongoing mutagenic process. Thus, extrachromosomal circular DNAs represent a multihit mutagenic process, with important functional and clinical implications for the origins of genomic remodeling in cancer.

  View details for DOI 10.1038/s41588-019-0547-z

  View details for Web of Science ID 000510822700007

  View details for PubMedID 31844324

  View details for PubMedCentralID PMC7008131

• Prohibitin promotes dedifferentiation and is a potential therapeutic target in neuroblastoma JCI INSIGHT MacArthur, I. C., Bei, Y., Garcia, H., Ortiz, M., Toedling, J., Klironomos, F., Ralff, J., Eggert, A., Schulte, J. H., Kentsis, A., Henssen, A. G. 2019; 4 (10)

  Abstract

  Gain of the long arm of chromosome 17 (17q) is a cytogenetic hallmark of high-risk neuroblastoma, yet its contribution to neuroblastoma pathogenesis remains incompletely understood. Combining whole-genome and RNA sequencing of neuroblastomas, we identified the prohibitin (PHB) gene as highly expressed in tumors with 17q gain. High PHB expression correlated with poor prognosis and was associated with loss of gene expression programs promoting neuronal development and differentiation. PHB depletion induced differentiation and apoptosis and slowed cell cycle progression of neuroblastoma cells, at least in part through impaired ERK1/2 activation. Conversely, ectopic expression of PHB was sufficient to increase proliferation of neuroblastoma cells and was associated with suppression of markers associated with neuronal differentiation and favorable neuroblastoma outcome. Thus, PHB is a 17q oncogene in neuroblastoma that promotes tumor cell proliferation, and de-differentiation.

  View details for DOI 10.1172/jci.insight.127130

  View details for Web of Science ID 000468146300015

  View details for PubMedID 30998507

  View details for PubMedCentralID PMC6542629

• Synergistic activity of BET inhibitor MK-8628 and PLK inhibitor Volasertib in preclinical models of medulloblastoma CANCER LETTERS Han, Y., Lindner, S., Bei, Y., Garcia, H., Timme, N., Althoff, K., Odersky, A., Schramm, A., Lissat, A., Kuenkele, A., Deubzer, H. E., Eggert, A., Schulte, J. H., Henssen, A. G. 2019; 445: 24-33

  Abstract

  Medulloblastoma is the most prevalent central nervous system tumor in children. Targeted treatment approaches for patients with high-risk medulloblastoma are needed as current treatment regimens are not curative in many cases and cause significant therapy-related morbidity. Medulloblastoma harboring MYC amplification have the most aggressive clinical course and worst outcome. Targeting the BET protein BRD4 has significant anti-tumor effects in preclinical models of MYC-amplified medulloblastoma, however, in most cases these are not curative. We here assessed the therapeutic efficacy of the orally bioavailable BRD4 inhibitor, MK-8628, in preclinical models of medulloblastoma. MK-8628 showed therapeutic efficacy against in vitro and in vivo models of MYC-amplified medulloblastoma by inducing apoptotic cell death and cell cycle arrest. Gene expression analysis of cells treated with MK-8628 showed that anti-tumor effects were accompanied by significant repression of MYC transcription as well as disruption of MYC-regulated transcriptional programs. Additionally, we found that targeting of MYC protein stability through pharmacological PLK1 inhibition showed synergistic anti-medulloblastoma effects when combined with MK-8628 treatment. Thus, MK-8628 is effective against preclinical high-risk medulloblastoma models and its effects can be enhanced through simultaneous targeting of PLK1.

  View details for DOI 10.1016/j.canlet.2018.12.012

  View details for Web of Science ID 000457949900003

  View details for PubMedID 30611741