Biology subjects

Unterberg, A.

Publications and source records attributed to Unterberg, A..

5 recordsLinked to original sources

bioRxiv2026

Prospective pan-cancer phosphoproteomics at clinical scale extends therapeutic options in precision oncology

Genomics-guided precision oncology has improved survival in cancer entities with actionable mutations but cannot capture oncogenic signaling that manifests at the protein level. Here, we report a prospective, real-world pan-cancer study profiling proteomes and phosphoproteomes of 1,998 tumor samples from adults and children with rare or advanced cancers enrolled in the German precision oncology programs DKFZ/NCT/DKTK MASTER, CATCH and INFORM and their molecular tumor boards (MTBs). We developed tumor proteome activity status (TOPAS) scores for 46 clinically relevant kinases, an immune activity score capturing antigen presentation and T-cell activation and identified therapeutically targetable cell-surface proteins for 94% of patients. These readouts enhance MTB recommendations by exposing actionable non-genomic kinase activity, refining interpretation of oncogenic genome alterations, and highlighting cell-surface treatment options. Three proof-of-concept analyses indicate clinical utility including kinase activity-stratified pazopanib response in sarcoma, immune activity score-tracked checkpoint-inhibitor outcomes pan-cancer, and a phosphoproteomic biomarker distinguishing EGFR-inhibitor response in chordoma.

cancer biology↗

bioRxiv2024

Tumor-Associated Macrophages in Meningiomas: An Independent Prognostic Factor for Poor Survival Outperforming the Benefits of T cells

BackgroundTumor-associated macrophages (TAMs) represent the main immune cell population in various brain malignancies. To elucidate their biological impact in the tumor microenvironment (TME) of meningiomas (MGMs), we assessed TAM numbers, activation state, malignancy- and survival-associated changes, as well as their association with tumor-infiltrating T lymphocytes (TILs). MethodsTAM infiltration was analyzed in a multicenter cohort of 195 clinically well-annotated cases (follow-up >5 years, n=120 newly-diagnosed and n=75 recurrent MGMs) enriched for higher-grade MGMs. TAMs and M2-TAMs were quantified by tissue cytometry on whole-tumor sections. Further, we assessed levels of 27 cyto- and chemokines in a subset of tissues (n=46 cases), and re-analyzed our previously published T cell infiltration (n=94 cases) and expanded microarray (n=97 cases) datasets. ResultsNewly-diagnosed MGMs showed a substantial but highly heterogeneous TAM infiltration that was four times higher than for TILs. Anti-inflammatory M2-TAMs were increased in higher WHO grade tumors and in recurrent MGMs. Importantly, high M2-TAM infiltration was associated with poor progression-free survival independent of other prognostic confounders and even mitigated the beneficial prognostic effect of TIL infiltration. Additional cytokine, gene expression and pathway analyses corroborated the presence of an immunosuppressive niche in M2-TAM-enriched MGMs. ConclusionsAltogether, higher numbers of TAMs and M2-TAMs appear to be a hallmark of clinically aggressive behavior in newly-diagnosed and recurrent MGMs. Unlike TILs, immunosuppressive TAMs seem to play a dominant negative role in the immunological landscape of MGMs, highlighting M2-TAMs to be an attractive treatment target for immunotherapeutic approaches. Translational Relevance of the StudyMeningiomas (MGMs) are typically regarded as benign neoplasms, however there is a substantial proportion of clinically aggressive tumors that are refractory to standard treatment modalities and demand for the development of novel therapeutic approaches such as immunotherapy. This is the first comprehensive study reporting malignancy- and progression-associated changes of tumor-associated macrophages (TAMs), their polarization state, their association with tumor-infiltrating T lymphocytes (TILs), and their impact on patient survival in a large multicenter cohort of 195 tumors containing substantial numbers of clinically aggressive cases. Notably, we identified higher numbers of immunosuppressive M2-TAMs as an independent prognostic factor for poor survival, overriding the beneficial prognostic effects of TILs. Thus, our data highlight an important role of immunosuppressive M2-TAMs on tumor malignancy and progression, and further suggest targeting macrophages as a treatment strategy to improve the success of immunotherapeutic approaches in MGMs. Key pointsO_LIMeningiomas are highly infiltrated by immunosuppressive M2-TAMs. C_LIO_LIHigh M2-TAM numbers are an independent negative prognostic factor for patient survival. C_LIO_LIHigh TAM infiltration mitigates the beneficial prognostic impact of TILs. C_LI

cancer biology↗

bioRxiv2024

Personalized Medicine for Meningiomas: Drug Screening on Tumor Organoids Exposes Therapeutic Vulnerabilities to HDAC1/2i Panobinostat

Managing aggressive meningiomas remains challenging due to limited treatment options besides surgical tumor removal and radiotherapy. To identify novel therapies for aggressive meningiomas, we established a multi-step drug screening workflow, focusing on targetable genes obtained from transcriptome data of highly aggressive grade 3 meningiomas. In vitro screening of 107 targeted drugs identified nine effective inhibitors. To study these drugs in a more natural environment, we established a standardized patient-derived tumor organoid (TO) model preserving accurately the original tissues genotype and phenotype. Individual drug responses were assessed in TOs from 60 molecularly characterized meningioma cases. Especially the FDA-approved epigenetic drug panobinostat demonstrated high antimeningioma efficacy in 70% of TOs, mediated through HDAC1/2 inhibition. In addition, treatment in an orthotopic in vivo model revealed a significantly improved survival. In a heavily pretreated patient suffering from an anaplastic meningioma, oral panobinostat treatment could delay the tumor growth rate. In search of the molecular mechanism underlying a potential intrinsic panobinostat resistance, we identified upregulation of the HDAC8-TGF{beta}-EMT axis in the TO model and subsequent HDAC8 depletion substantially increased the sensitivity to panobinostat. These data highlight the utility of personalized drug screenings on TOs to identify suitable drug targets and inhibitors for a more effective treatment of clinically aggressive meningiomas and help to advance our understanding of counteracting resistance mechanisms. One Sentence SummaryThis study provides strong in vitro, in vivo, ex vivo, and patient evidence for the efficacy of the HDACi panobinostat to treat clinically aggressive meningiomas and uncovered a potential intrinsic resistance mechanism by activation of the HDAC8-TGF{beta}-EMT axis.

cancer biology↗

bioRxiv2022

Reprogramming M2-polarized patient-derived glioblastoma associated microglia/macrophages via CSF1R inhibition

Targeting immunosuppressive and protumorigenic glioblastoma-associated macrophages and microglial cells (GAMs) holds great potential to improve patient outcomes. Although CSF1R has emerged as a promising target to reprogram anti-inflammatory M2-like GAMs, relevant treatment data on human, tumor-educated GAMs and innovative patient-derived 3D tumor organoid models to study the influence on adaptive immunity and the effectiveness of treatment in a complex and entirely autologous setting are largely lacking. We performed a comprehensive phenotypical, transcriptional and functional analysis of primary, patient-derived GAMs upon treatment with the CSF1R-targeting drugs PLX3397, BLZ945, and GW2580. The most effective reprogramming of GAMs was observed upon GW2580 treatment, which led to a downregulation of M2-related markers and signaling pathways, while M1-like markers, phagocytosis, and T-cell killing were substantially increased. Moreover, treatment of patient-derived glioblastoma organoids with GW2580 confirmed successful reprogramming together with reduced tumor cell proliferation, indicating that treatment with GW2580 could be an important pillar in the future therapy of GBM.

cancer biology↗

bioRxiv2021

Integrated phospho-proteogenomic and single-cell transcriptomic analysis of meningiomas establishes robust subtyping and reveals subtype-specific immune invasion

Meningiomas are the most frequent primary intracranial tumors. They can follow a wide clinical spectrum from benign to highly aggressive clinical course. No specific therapy exists for refractory cases or cases not amenable to resection and radiotherapy. Identification of risk of recurrence and malignant transformation for the individual patients is challenging. However, promising molecular markers and prognostic subgrouping by DNA methylation are emerging. Still, the biological underpinnings of these diagnostic subgroups are elusive, and, consequently, no novel therapeutic options arise thereof. Here we establish robust subgroups across the full landscape of meningiomas, consistent through DNA methylation, mutations, the transcriptomic, proteomic and phospho-proteomic level. Pronounced proliferative stress and DNA damage repair signals in malignant cells and in clusters exclusive to recurrent tumors are in line with their higher mitotic activity, but also provide an explanation for the accumulation of genomic instability in anaplastic meningiomas. Although homozygous deletion of CDKN2A/B is a diagnostic marker of high-grade meningioma, the expression of its gene product increased from low to non-deleted high-grade cases. Differences between subgroups in lymphocyte and myeloid cell infiltration, representing a majority of tumor mass in low-grade NF2 tumors, could be assigned to cluster-specific interaction with tumor cells. Activation to a more proinflammatory phenotype and decreased infiltration of myeloid cells in high-grade cases correlated with lower expression of CSF1, located on chromosome arm 1p, whose deletion is known as prognostic marker, with no proposed mechanism before. Our results demonstrate a robust molecular subclassification of a tumor type across multiple layers, provide insight into heterogeneous growth dynamics despite shared pathognomonic mutations, and highlight immune infiltration modulation as a novel target for meningioma therapy.

genomics↗