PhD position in the Department Neuropathology, Heidelberg University Hospital, Focus C06

Link to job description

Contact and Application: Please apply by sending a CV to David Reuss at David.Reuss@med.uni-heidelberg.de.

Applications will be accepted via email.

Neuropathology
OA PD Dr. med. David Reuss
Gebäude 6224 Ebene 00
Im Neuenheimer Feld 224
69120 Heidelberg

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Dear Members and Friends of UNITE,

We are happy to provide you with our 2nd UNITE Newsletter today!

The start of our second funding phase was less than a year ago, but we can already look back on many scientific and personal highlights. We are excited to share some of these with you today.

Moreover, we will give you an overview of upcoming workshops and UNITE Events and provide further information on the UNITE travel grants. Stay tuned and enjoy reading the UNITE Spring Edition of our Newsletter!

Best wishes,
The UNITE Project Management Team

UNITE_Newsletter_202402

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Research findings related to UNITE work package A03

Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. However, the determination of TM-interconnectivity in individual tumors is challenging and the impact on patient survival unresolved. Here, we establish a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells using a dye uptake methodology, and validate it with recording of cellular calcium epochs and clinical correlations. Astrocyte-like and mesenchymal-like GB cells have the highest connectivity signature scores in scRNA-sequenced patient-derived xenografts and patient samples. In large GB cohorts, TM-network connectivity correlates with the mesenchymal subtype and dismal patient survival. CHI3L1 gene expression serves as a robust molecular marker of connectivity and functionally influences TM networks. The connectivity signature allows insights into brain tumor biology, provides a proof-of-principle that tumor cell TM-connectivity is relevant for patients’ prognosis, and serves as a robust prognostic biomarker.

Link to Publication

Ling Hai, Dirk C. Hoffmann, Robin J. Wagener, Daniel D. Azorin, David Hausmann, Ruifan Xie, Magnus-Carsten Huppertz, Julien Hiblot, Philipp Sievers, Sophie Heuer*, Jakob Ito, Gina Cebulla, Alexandros Kourtesakis, Leon D. Kaulen, Miriam Ratliff*, Henriette Mandelbaum, Erik Jung, Ammar Jabali, Sandra Horschitz, Kati J. Ernst, Denise Reibold, Uwe Warnken, Varun Venkataramani*, Rainer Will, Mario L. Suvà, Christel Herold-Mende*, Felix Sahm*, Frank Winkler*, Matthias Schlesner*, Wolfgang Wick* & Tobias Kessler*. A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1. Nat Commun. 2024 15, 968. * UNITE Principal Investigators

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Research findings related to UNITE work package A01

Diffuse gliomas, particularly glioblastomas, are incurable brain tumours. They are characterized by networks of interconnected brain tumour cells that communicate via Ca2+ transients. However, the networks’ architecture and communication strategy and how these influence tumour biology remain unknown. Here we describe how glioblastoma cell networks include a small, plastic population of highly active glioblastoma cells that display rhythmic Ca2+ oscillations and are particularly connected to others. Their autonomous periodic Ca2+ transients preceded Ca2+ transients of other network-connected cells, activating the frequency-dependent MAPK and NF-κB pathways. Mathematical network analysis revealed that glioblastoma network topology follows scale-free and small-world properties, with periodic tumour cells frequently located in network hubs. This network design enabled resistance against random damage but was vulnerable to losing its key hubs. Targeting of autonomous rhythmic activity by selective physical ablation of periodic tumour cells or by genetic or pharmacological interference with the potassium channel KCa3.1 (also known as IK1, SK4 or KCNN4) strongly compromised global network communication. This led to a marked reduction of tumour cell viability within the entire network, reduced tumour growth in mice and extended animal survival. The dependency of glioblastoma networks on periodic Ca2+ activity generates a vulnerability that can be exploited for the development of novel therapies, such as with KCa3.1-inhibiting drugs.

LINK TO PUBLICATION

Hausmann D, Hoffmann DC, Venkataramani V*, Jung E, Horschitz S, Tetzlaff SK, Jabali A, Hai L, Kessler T*, Azorín DD, Weil S*, Kourtesakis A, Sievers P, Habel A, Breckwoldt MO*, Karreman M*, Ratliff M*, Messmer JM, Yang Y, Reyhan E, Wendler S, Loeb C, Mayer C, Figarella K, Osswald M, Solecki G, Sahm F*, Garaschuk O, Kuner T, Koch P, Schlesner M*, Wick W*, Winkler F*. Autonomous rhythmic activity in glioma networks drives brain tumor growth. Nature. 2023 Jan 613 7942 179 186. *UNITE Principle Investigators

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Research findings related to UNITE work package A01

The nervous system governs both ontogeny and oncology. Regulating organogenesis during development, maintaining homeostasis, and promoting plasticity throughout life, the nervous system plays parallel roles in the regulation of cancers. Foundational discoveries have elucidated direct paracrine and electrochemical communication between neurons and cancer cells, as well as indirect interactions through neural effects on the immune system and stromal cells in the tumor microenvironment in a wide range of malignancies. Nervous system-cancer interactions can regulate oncogenesis, growth, invasion and metastatic spread, treatment resistance, stimulation of tumor-promoting inflammation, and impairment of anti-cancer immunity. Progress in cancer neuroscience may create an important new pillar of cancer therapy.

LINK TO PUBLICATION

Winkler F*, Venkatesh H S, Amit M, Batchelor T, Demir I E, Deneen B, Gutmann D H, Hervey-Jumper S, Kuner T, Mabbott D, Platten M*, Rolls A, Sloan E K, Wang T C, Wick W*, Venkataramani V*, Monje M. Cancer neuroscience: state of the field, emerging directions. Cell. 2023 186 1689 707. *UNITE Principle Investigators

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Research findings related to UNITE work package A01

Purpose: The EORTC-26101 study was a randomized phase II and III clinical trial of bevacizumab in combination with lomustine versus lomustine alone in progressive glioblastoma. Other than for progression-free survival (PFS), there was no benefit from addition of bevacizumab for overall survival (OS). However, molecular data allow for the rare opportunity to assess prognostic biomarkers from primary surgery for their impact in progressive glioblastoma.

Experimental design: We analyzed DNA methylation array data and panel sequencing from 170 genes of 380 tumor samples of the EORTC-26101 study. These patients were comparable with the overall study cohort in regard to baseline characteristics, study treatment, and survival.

Results: Of patients’ samples, 295/380 (78%) were classified into one of the main glioblastoma groups, receptor tyrosine kinase (RTK)1, RTK2 and mesenchymal. There were 10 patients (2.6%) with isocitrate dehydrogenase mutant tumors in the biomarker cohort. Patients with RTK1 and RTK2 classified tumors had lower median OS compared with mesenchymal (7.6 vs. 9.2 vs. 10.5 months). O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation was prognostic for PFS and OS. Neurofibromin (NF)1 mutations were predictive of response to bevacizumab treatment.

Conclusions: Thorough molecular classification is important for brain tumor clinical trial inclusion and evaluation. MGMT promoter methylation and RTK1 classifier assignment were prognostic in progressive glioblastoma. NF1 mutation may be a predictive biomarker for bevacizumab treatment.

LINK TO PUBLICATION

Kessler T*, Schrimpf D, Doerner L, Hai L*, Kaulen LD, Ito J, van den Bent M, Taphoorn M, Brandes AA, Idbaih A, Dômont J, Clement PM, Campone M, Bendszus M*, von Deimling A*, Sahm F*, Platten M*, Wick W*, Wick A. Prognostic Markers of DNA Methylation and Next-Generation Sequencing in Progressive Glioblastoma from the EORTC-26101 Trial. Clin Cancer Res. 2023 Jul 26; CCR-23-0926. doi: 10.1158/1078-0432.CCR-23-0926. *UNITE Principle Investigators

Primary brain tumors, particularly glioblastoma, grow aggressively and are incurable until today. We have discovered novel mechanisms of tumor biology and treatment resistance that are related to the emerging field of “Cancer Neuroscience”: tumor cells hijack neural machanisms to thrive, and communicate with neurons of the normal brain. Brain tumor resistance against established therapies seems related to these mechanisms. However, it is particularly not clear how vivid intercellular communication patterns via calcium waves (Hausmann et al., Nature 2023) exactly contribute to resistance, and how this can be overcome.

The aim of this PhD project is to further explore how calcium communications patterns in glioma networks change after treatment (surgery, radiotherapy, chemotherapy), how they reflect the therapy resistance biologically, and which molecular mechanisms are in place. Calcium communication inhibiting compounds will be further tested and combined with therapy to overcome treatment resistance. For this project, our two-photon in vivo microscopy model and further manifold state-of-the-art techniques will be taught and used, and further development of techniques and concepts are encouraged and supported.

As part of the Comprehensive Research Center (CRC) 1389 “Unite Glioblastoma” network, our group is interested in translational glioblastoma research aiming to bring insights from basic research models to clinical applicability as new treatments for patients. The Winkler Lab is internationally renowned for developing the field of Cancer Neuroscience, with a methodological focus on intravital imaging (Osswald et al., Nature 2015, Weil et al., Neuro Oncology 2017, Venkataramani et al., Nature 2019, Venkataramani et al., Cell 2022, Hausmann et al., Nature 2023).

For more information and the full job posting, click here.

EANO Guideline 2

UNITE  towards clinical implementation

In response to major changes in diagnostic algorithms and the publication of mature results from various large clinical trials, the European Association of Neuro-Oncology (EANO) recognized the need to provide updated guidelines for the diagnosis and management of adult patients with diffuse gliomas. Through these evidence-based guidelines, a task force of EANO provides recommendations for the diagnosis, treatment and follow-up of adult patients with diffuse gliomas. The diagnostic component is based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System and the subsequent recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumour Taxonomy – Not Officially WHO (cIMPACT-NOW). With regard to therapy, we formulated recommendations based on the results from the latest practice-changing clinical trials and also provide guidance for neuropathological and neuroradiological assessment. In these guidelines, we define the role of the major treatment modalities of surgery, radiotherapy and systemic pharmacotherapy, covering current advances and cognizant that unnecessary interventions and expenses should be avoided. This document is intended to be a source of reference for professionals involved in the management of adult patients with diffuse gliomas, for patients and caregivers, and for health-care providers.

 

LINK TO PUBLICATION

Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, Bendszus M*, Balana C, Chinot O, Dirven L, French P, Hegi ME, Jakola AS, Platten M*, Roth P, Rudà R, Short S, Smits M, Taphoorn MJB, von Deimling A*, Westphal M, Soffietti R, Reifenberger G, Wick W*. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2020 Dec 8. doi: 10.1038/s41571-020-00447-z. Online ahead of print.Nat Rev Clin Oncol. 2020.PMID: 33293629

*UNITE Principle Investigators

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Research findings related to UNITE work package C04

Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid. It associates with reduced survival in glioma patients, promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice. Immune checkpoint blockade (ICB) induces IDO1 and IL4I1. As IDO1 inhibitors do not block IL4I1, IL4I1 may explain the failure of clinical studies combining ICB with IDO1 inhibition. Taken together, IL4I1 blockade opens new avenues for cancer therapy.

LINK TO PUBLICATION

Sadik A, Somarribas Patterson LF, Öztürk S, Mohapatra SR, Panitz V, Secker PF, Pfänder P, Loth S, Salem H, Prentzell MT, Berdel B, Iskar M, Faessler E, Reuter F, Kirst I, Kalter V, Foerster KI, Jäger E, Guevara CR, Sobeh M, Hielscher T, Poschet G, Reinhardt A, Hassel JC, Zapatka M, Hahn U, von Deimling A*, Hopf C*, Schlichting R, Escher BI, Burhenne J, Haefeli WE*, Ishaque N, Böhme A, Schäuble S, Thedieck K, Trump S, Seiffert M, Opitz CA.*. IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression. Cell. 2020 Aug 17:S0092-8674(20)30946-6. *UNITE Principle Investigators

Research findings related to UNITE work package B01

Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated glioblastomas showing response. Modeling patient-individual resistance is challenging due to the lack of predictive biomarkers and limited accessibility of tissue for serial biopsies. Here, Michael Platten et al. investigate resistance mechanisms to anti-PD-1 and anti-CTLA-4 therapy in syngeneic hypermutated experimental gliomas and show a clear dichotomy and acquired immune heterogeneity in ICB-responder and non-responder tumors. They made use of this dichotomy to establish a radiomic signature predicting tumor regression after pseudoprogression induced by ICB therapy based on serial magnetic resonance imaging. They provide evidence that macrophage-driven ICB resistance is established by CD4 T cell suppression and Treg expansion in the tumor microenvironment via the PD-L1/PD-1/CD80 axis. These findings uncover an unexpected heterogeneity of response to ICB in strictly syngeneic tumors and provide a rationale for targeting PD-L1-expressing tumor-associated macrophages to overcome resistance to ICB.

LINK TO PUBLICATION

Aslan K, Turco V, Blobner J, Sonner JK, Liuzzi AR, Núñez NG, De Feo D, Kickingereder P*, Fischer M, Green E, Sadik A, Friedrich M, Sanghvi K, Kilian M, Cichon F, Wolf L, Jähne K, von Landenberg A, Bunse L*, Sahm F*, Schrimpf D, Meyer J, Alexander A, Brugnara G, Röth R, Pfleiderer K, Niesler B, von Deimling A, Opitz C, Breckwoldt MO, Heiland S, Bendszus M*, Wick W*, Becher B, Platten M*. Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas. Nat Commun. 2020 Feb 18;11(1):931. *UNITE Principle Investigators