bims-malgli 2024-04-28 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2024–04–28
thirteen papers selected by
Oltea Sampetrean, Keio University

Spatial transcriptomics reveals segregation of tumor cell states in glioblastoma and marked immunosuppression within the perinecrotic niche.
All-trans retinoic acid induces durable tumor immunity in IDH-mutant gliomas by rescuing transcriptional repression of the CRBP1-retinoic acid axis.
Integrative spatial analysis reveals a multi-layered organization of glioblastoma.
Molecular biology and novel therapeutics for IDH mutant gliomas: The new era of IDH inhibitors.
RAPID resistance to BET inhibitors is mediated by FGFR1 in glioblastoma.
ID1high/activin Ahigh glioblastoma cells contribute to resistance to anti-angiogenesis therapy through malformed vasculature.
Multiplexed single-cell lineage tracing of mitotic kinesin inhibitor resistance in glioblastoma.
RNA splicing analysis deciphers developmental hierarchies and reveals therapeutic targets in adult glioma.
Profiling the molecular and clinical landscape of glioblastoma utilizing the Oncology Research Information Exchange Network brain cancer database.
Classifying glioma via liquid biopsy--progress towards an unmet clinical need.
SEOM-GEINO clinical guidelines for grade 2 gliomas (2023).
A heterogeneous pharmaco-transcriptomic landscape induced by targeting a single oncogenic kinase.
Simultaneous boost radiotherapy versus conventional dose radiotherapy for patients with newly diagnosed glioblastoma: a multi-institutional analysis.

Acta Neuropathol Commun. 2024 Apr 22. 12(1): 64

Spatial transcriptomics reveals segregation of tumor cell states in glioblastoma and marked immunosuppression within the perinecrotic niche.

Mengyi Liu, Zhicheng Ji, Vaibhav Jain, Vanessa L Smith, Emily Hocke, Anoop P Patel, Roger E McLendon, David M Ashley, Simon G Gregory, Giselle Y López.

  Glioblastoma (GBM) remains an untreatable malignant tumor with poor patient outcomes, characterized by palisading necrosis and microvascular proliferation. While single-cell technology made it possible to characterize different lineage of glioma cells into neural progenitor-like (NPC-like), oligodendrocyte-progenitor-like (OPC-like), astrocyte-like (AC-like) and mesenchymal like (MES-like) states, it does not capture the spatial localization of these tumor cell states. Spatial transcriptomics empowers the study of the spatial organization of different cell types and tumor cell states and allows for the selection of regions of interest to investigate region-specific and cell-type-specific pathways. Here, we obtained paired 10x Chromium single-nuclei RNA-sequencing (snRNA-seq) and 10x Visium spatial transcriptomics data from three GBM patients to interrogate the GBM microenvironment. Integration of the snRNA-seq and spatial transcriptomics data reveals patterns of segregation of tumor cell states. For instance, OPC-like tumor and NPC-like tumor significantly segregate in two of the three samples. Our differentially expressed gene and pathway analyses uncovered significant pathways in functionally relevant niches. Specifically, perinecrotic regions were more immunosuppressive than the endogenous GBM microenvironment, and perivascular regions were more pro-inflammatory. Our gradient analysis suggests that OPC-like tumor cells tend to reside in areas closer to the tumor vasculature compared to tumor necrosis, which may reflect increased oxygen requirements for OPC-like cells. In summary, we characterized the localization of cell types and tumor cell states, the gene expression patterns, and pathways in different niches within the GBM microenvironment. Our results provide further evidence of the segregation of tumor cell states and highlight the immunosuppressive nature of the necrotic and perinecrotic niches in GBM.

Keywords:  Glioblastoma; Perinecrotic niche; Perivascular niche; Single-cell sequencing; Spatial transcriptomics; Tumor microenvironment

DOI:  https://doi.org/10.1186/s40478-024-01769-0
bioRxiv. 2024 Apr 13. pii: 2024.04.09.588752. [Epub ahead of print]

All-trans retinoic acid induces durable tumor immunity in IDH-mutant gliomas by rescuing transcriptional repression of the CRBP1-retinoic acid axis.

Aparna Rao, Xiaoran Zhang, Anthony R Cillo, Jonathan H Sussman, Poorva Sandlesh, Antonio Corral Tarbay, Arka N Mallela, Carly Cardello, Katharine Krueger, Jessica Xu, Alex Li, Jason Xu, Jonathan Patterson, Ebrar Akca, Angelo Angione, Emade Jaman, Wi Jin Kim, Jordan Allen, Abhishek Venketeswaran, Pascal O Zinn, Robert Parise, Jan Beumer, Anette Duensing, Eric C Holland, Robert Ferris, Stephen J Bagley, Tullia C Bruno, Dario A A Vignali, Sameer Agnihotri, Nduka M Amankulor.

Diffuse gliomas are epigenetically dysregulated, immunologically cold, and fatal tumors characterized by mutations in isocitrate dehydrogenase (IDH). Although IDH mutations yield a uniquely immunosuppressive tumor microenvironment, the regulatory mechanisms that drive the immune landscape of IDH mutant (IDHm) gliomas remain unknown. Here, we reveal that transcriptional repression of retinoic acid (RA) pathway signaling impairs both innate and adaptive immune surveillance in IDHm glioma through epigenetic silencing of retinol binding protein 1 (RBP1) and induces a profound anti-inflammatory landscape marked by loss of inflammatory cell states and infiltration of suppressive myeloid phenotypes. Restorative retinoic acid therapy in murine glioma models promotes clonal CD4 + T cell expansion and induces tumor regression in IDHm, but not IDH wildtype (IDHwt), gliomas. Our findings provide a mechanistic rationale for RA immunotherapy in IDHm glioma and is the basis for an ongoing investigator-initiated, single-center clinical trial investigating all-trans retinoic acid (ATRA) in recurrent IDHm human subjects.

DOI: https://doi.org/10.1101/2024.04.09.588752
Cell. 2024 Apr 16. pii: S0092-8674(24)00320-9. [Epub ahead of print]

Integrative spatial analysis reveals a multi-layered organization of glioblastoma.

Alissa C Greenwald, Noam Galili Darnell, Rouven Hoefflin, Dor Simkin, Christopher W Mount, L Nicolas Gonzalez Castro, Yotam Harnik, Sydney Dumont, Dana Hirsch, Masashi Nomura, Tom Talpir, Merav Kedmi, Inna Goliand, Gioele Medici, Julie Laffy, Baoguo Li, Vamsi Mangena, Hadas Keren-Shaul, Michael Weller, Yoseph Addadi, Marian C Neidert, Mario L Suvà, Itay Tirosh.

  Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics, spatial proteomics, and computational approaches to define glioma cellular states and uncover their organization. We find three prominent modes of organization. First, gliomas are composed of small local environments, each typically enriched with one major cellular state. Second, specific pairs of states preferentially reside in proximity across multiple scales. This pairing of states is consistent across tumors. Third, these pairwise interactions collectively define a global architecture composed of five layers. Hypoxia appears to drive the layers, as it is associated with a long-range organization that includes all cancer cell states. Accordingly, tumor regions distant from any hypoxic/necrotic foci and tumors that lack hypoxia such as low-grade IDH-mutant glioma are less organized. In summary, we provide a conceptual framework for the organization of cellular states in glioma, highlighting hypoxia as a long-range tissue organizer.

Keywords:  glioblastoma; glioma; hypoxia; intratumor heterogeneity; spatial proteomics; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.cell.2024.03.029
Biochim Biophys Acta Rev Cancer. 2024 Apr 21. pii: S0304-419X(24)00033-7. [Epub ahead of print]1879(3): 189102

Molecular biology and novel therapeutics for IDH mutant gliomas: The new era of IDH inhibitors.

Yosuke Kitagawa, Ami Kobayashi, Daniel P Cahill, Hiroaki Wakimoto, Shota Tanaka.

  Gliomas with Isocitrate dehydrogenase (IDH) mutation represent a discrete category of primary brain tumors with distinct and unique characteristics, behaviors, and clinical disease outcomes. IDH mutations lead to aberrant high-level production of the oncometabolite D-2-hydroxyglutarate (D-2HG), which act as a competitive inhibitor of enzymes regulating epigenetics, signaling pathways, metabolism, and various other processes. This review summarizes the significance of IDH mutations, resulting upregulation of D-2HG and the associated molecular pathways in gliomagenesis. With the recent finding of clinically effective IDH inhibitors in these gliomas, this article offers a comprehensive overview of the new era of innovative therapeutic approaches based on mechanistic rationales, encompassing both completed and ongoing clinical trials targeting gliomas with IDH mutations.

Keywords:  D2-hydroxyglutarate (D2-HG); Glioma; Isocitrate dehydrogenase (IDH)

DOI:  https://doi.org/10.1016/j.bbcan.2024.189102
Sci Rep. 2024 04 23. 14(1): 9284

RAPID resistance to BET inhibitors is mediated by FGFR1 in glioblastoma.

Anna M Jermakowicz, Alison M Kurimchak, Katherine J Johnson, Florence Bourgain-Guglielmetti, Simon Kaeppeli, Maurizio Affer, Hari Pradhyumnan, Robert K Suter, Winston Walters, Maria Cepero, James S Duncan, Nagi G Ayad.

Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets in several cancers including the most common malignant adult brain tumor glioblastoma (GBM). Multiple small molecule inhibitors of BET proteins have been utilized in preclinical and clinical studies. Unfortunately, BET inhibitors have not shown efficacy in clinical trials enrolling GBM patients. One possible reason for this may stem from resistance mechanisms that arise after prolonged treatment within a clinical setting. However, the mechanisms and timeframe of resistance to BET inhibitors in GBM is not known. To identify the temporal order of resistance mechanisms in GBM we performed quantitative proteomics using multiplex-inhibitor bead mass spectrometry and demonstrated that intrinsic resistance to BET inhibitors in GBM treatment occurs rapidly within hours and involves the fibroblast growth factor receptor 1 (FGFR1) protein. Additionally, small molecule inhibition of BET proteins and FGFR1 simultaneously induces synergy in reducing GBM tumor growth in vitro and in vivo. Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM.

DOI: https://doi.org/10.1038/s41598-024-60031-8
Cell Death Dis. 2024 Apr 24. 15(4): 292

ID1high/activin Ahigh glioblastoma cells contribute to resistance to anti-angiogenesis therapy through malformed vasculature.

Sang-Hun Choi, Junseok Jang, Yoonji Kim, Cheol Gyu Park, Seon Yong Lee, Hyojin Kim, Hyunggee Kim.

Although bevacizumab (BVZ), a representative drug for anti-angiogenesis therapy (AAT), is used as a first-line treatment for patients with glioblastoma (GBM), its efficacy is notably limited. Whereas several mechanisms have been proposed to explain the acquisition of AAT resistance, the specific underlying mechanisms have yet to be sufficiently ascertained. Here, we established that inhibitor of differentiation 1 (ID1)high/activin Ahigh glioblastoma cell confers resistance to BVZ. The bipotent effect of activin A during its active phase was demonstrated to reduce vasculature dependence in tumorigenesis. In response to a temporary exposure to activin A, this cytokine was found to induce endothelial-to-mesenchymal transition via the Smad3/Slug axis, whereas prolonged exposure led to endothelial apoptosis. ID1 tumors showing resistance to BVZ were established to be characterized by a hypovascular structure, hyperpermeability, and scattered hypoxic regions. Using a GBM mouse model, we demonstrated that AAT resistance can be overcome by administering therapy based on a combination of BVZ and SB431542, a Smad2/3 inhibitor, which contributed to enhancing survival. These findings offer valuable insights that could contribute to the development of new strategies for treating AAT-resistant GBM.

DOI: https://doi.org/10.1038/s41419-024-06678-7
Cell Rep. 2024 Apr 21. pii: S2211-1247(24)00467-4. [Epub ahead of print]43(5): 114139

Multiplexed single-cell lineage tracing of mitotic kinesin inhibitor resistance in glioblastoma.

Yim Ling Cheng, Matei A Banu, Wenting Zhao, Steven S Rosenfeld, Peter Canoll, Peter A Sims.

  Glioblastoma (GBM) is a deadly brain tumor, and the kinesin motor KIF11 is an attractive therapeutic target with roles in proliferation and invasion. Resistance to KIF11 inhibitors, which has mainly been studied in animal models, presents significant challenges. We use lineage-tracing barcodes and single-cell RNA sequencing to analyze resistance in patient-derived GBM neurospheres treated with ispinesib, a potent KIF11 inhibitor. Similar to GBM progression in patients, untreated cells lose their neural lineage identity and become mesenchymal, which is associated with poor prognosis. Conversely, cells subjected to long-term ispinesib treatment exhibit a proneural phenotype. We generate patient-derived xenografts and show that ispinesib-resistant cells form less aggressive tumors in vivo, even in the absence of drug. Moreover, treatment of human ex vivo GBM slices with ispinesib demonstrates phenotypic alignment with in vitro responses, underscoring the clinical relevance of our findings. Finally, using retrospective lineage tracing, we identify drugs that are synergistic with ispinesib.

Keywords:  CP: Cancer; CP: Cell biology; drug resistance; glioblastoma; mitotic kinesins; multiplexed lineage tracing; single-cell genomics

DOI:  https://doi.org/10.1016/j.celrep.2024.114139
J Clin Invest. 2024 Apr 25. pii: e173789. [Epub ahead of print]

RNA splicing analysis deciphers developmental hierarchies and reveals therapeutic targets in adult glioma.

Xiao Song, Deanna Tiek, Shunichiro Miki, Tianzhi Huang, Minghui Lu, Anshika Goenka, Rebeca P Iglesia, Xiaozhou Yu, Runxin Wu, Maya N Walker, Chang Zeng, Hardik Shah, Shao Huan Samuel Weng, Allen Huff, Wei Zhang, Tomoyuki Koga, Christopher G Hubert, Craig M Horbinski, Frank F Furnari, Bo Hu, Shi-Yuan Cheng.

  Widespread alterations in RNA alternative splicing (AS) have been identified in adult gliomas. However, their regulatory mechanism, biological significance, and therapeutic potential remain largely elusive. Here, using a computational approach with both bulk and single cell RNA-sequencing, we uncover a prognostic AS signature linked with neural developmental hierarchies. Using advanced iPSC glioma models driven by glioma driver mutations, we show that this AS signature could be enhanced by EGFRvIII and inhibited by in situ IDH1 mutation. Functional validation of two isoform switching events in CERS5 and MPZL1 shows regulations of sphingolipid metabolism and SHP2 signaling, respectively. Analysis of upstream RNA binding proteins reveals PTBP1 as a key regulator of the AS signature where targeting of PTBP1 suppresses tumor growth and promotes the expression of a neuron marker TUJ1 in glioma stem-like cells. Overall, our data highlights the role of AS in impacting glioma malignance and heterogeneity and its potential as a therapeutic vulnerability for treating adult gliomas.

Keywords:  Brain cancer; Cell biology; Molecular biology; Oncology; RNA processing

DOI:  https://doi.org/10.1172/JCI173789
Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae046

Profiling the molecular and clinical landscape of glioblastoma utilizing the Oncology Research Information Exchange Network brain cancer database.

Alexandra N Demetriou, Frances Chow, David W Craig, Michelle G Webb, D Ryan Ormond, James Battiste, Arnab Chakravarti, Howard Colman, John L Villano, Bryan P Schneider, James K C Liu, Michelle L Churchman, Gabriel Zada.

   Background: Glioblastoma exhibits aggressive growth and poor outcomes despite treatment, and its marked variability renders therapeutic design and prognostication challenging. The Oncology Research Information Exchange Network (ORIEN) database contains complementary clinical, genomic, and transcriptomic profiling of 206 glioblastoma patients, providing opportunities to identify novel associations between molecular features and clinical outcomes.
Methods: Survival analyses were performed using the Logrank test, and clinical features were evaluated using Wilcoxon and chi-squared tests with q-values derived via Benjamini-Hochberg correction. Mutational analyses utilized sample-level enrichments from whole exome sequencing data, and statistical tests were performed using the one-sided Fisher Exact test with Benjamini-Hochberg correction. Transcriptomic analyses utilized a student's t-test with Benjamini-Hochberg correction. Expression fold changes were processed with Ingenuity Pathway Analysis to determine pathway-level alterations between groups.
Results: Key findings include an association of MUC17, SYNE1, and TENM1 mutations with prolonged overall survival (OS); decreased OS associated with higher epithelial growth factor receptor (EGFR) mRNA expression, but not with EGFR amplification or mutation; a 14-transcript signature associated with OS > 2 years; and 2 transcripts associated with OS < 1 year.
Conclusions: Herein, we report the first clinical, genomic, and transcriptomic analysis of ORIEN glioblastoma cases, incorporating sample reclassification under updated 2021 diagnostic criteria. These findings create multiple avenues for further investigation and reinforce the value of multi-institutional consortia such as ORIEN in deepening our knowledge of intractable diseases such as glioblastoma.

Keywords:  EGFR; genomics; glioblastoma; survival; transcriptomics

DOI:  https://doi.org/10.1093/noajnl/vdae046
Clin Cancer Res. 2024 Apr 23.

Classifying glioma via liquid biopsy--progress towards an unmet clinical need.

Kalil G Abdullah.

The diagnosis and classification of glioma by liquid biopsy represents a critical unmet need in neuro oncology. A recent study demonstrates targeted next generation sequencing (NGS) of cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) as an evolving option for liquid biopsy in patients with glioma.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-0423
Clin Transl Oncol. 2024 Apr 25.

SEOM-GEINO clinical guidelines for grade 2 gliomas (2023).

María Ángeles Vaz-Salgado, Belén Cigarral García, Isaura Fernández Pérez, Beatriz Jiménez Munárriz, Paula Sampedro Domarco, Ainhoa Hernández González, María Vieito Villar, Raquel Luque Caro, María Luisa Villamayor Delgado, Juan Manuel Sepúlveda Sánchez.

  The 2021 World Health Organization (WHO) classification has updated the definition of grade 2 gliomas and the presence of isocitrate dehydrogenase (IDH) mutation has been deemed the cornerstone of diagnosis. Though slow-growing and having a low proliferative index, grade 2 gliomas are incurable by surgery and complementary treatments are vital to improving prognosis. This guideline provides recommendations on the multidisciplinary treatment of grade 2 astrocytomas and oligodendrogliomas based on the best evidence available.

Keywords:  Astrocytoma; Guideline; IDH mutation; Low-grade glioma; Neuro-oncology; Oligodendroglioma

DOI:  https://doi.org/10.1007/s12094-024-03456-x
bioRxiv. 2024 Apr 10. pii: 2024.04.08.587960. [Epub ahead of print]

A heterogeneous pharmaco-transcriptomic landscape induced by targeting a single oncogenic kinase.

Ross M Giglio, Nicholas Hou, Adeya Wyatt, Justin Hong, Lingting Shi, Mathini Vaikunthan, Henry Fuchs, Jose Pomarino Nima, Seth W Malinowski, Keith L Ligon, José R McFaline-Figueroa, Nir Yosef, Elham Azizi, José L McFaline-Figueroa.

Over-activation of the epidermal growth factor receptor (EGFR) is a hallmark of glioblastoma. However, EGFR-targeted therapies have led to minimal clinical response. While delivery of EGFR inhibitors (EGFRis) to the brain constitutes a major challenge, how additional drug-specific features alter efficacy remains poorly understood. We apply highly multiplex single-cell chemical genomics to define the molecular response of glioblastoma to EGFRis. Using a deep generative framework, we identify shared and drug-specific transcriptional programs that group EGFRis into distinct molecular classes. We identify programs that differ by the chemical properties of EGFRis, including induction of adaptive transcription and modulation of immunogenic gene expression. Finally, we demonstrate that pro-immunogenic expression changes associated with a subset of tyrphostin family EGFRis increase the ability of T-cells to target glioblastoma cells.

DOI: https://doi.org/10.1101/2024.04.08.587960
Sci Rep. 2024 04 23. 14(1): 9283

Simultaneous boost radiotherapy versus conventional dose radiotherapy for patients with newly diagnosed glioblastoma: a multi-institutional analysis.

Seiya Takano, Natsuo Tomita, Mayu Kuno, Masanari Niwa, Akira Torii, Taiki Takaoka, Nozomi Kita, Dai Okazaki, Shintaro Yamamoto, Tatsuya Kawai, Chikao Sugie, Yasutaka Ogawa, Kenichi Matsumoto, Kaoru Uchiyama, Shinya Otsuka, Tooru Matsui, Akifumi Miyakawa, Tomoki Mizuno, Masato Iida, Motoki Tanikawa, Mitsuhito Mase, Akio Hiwatashi.

We compared survival outcomes of high-dose concomitant boost radiotherapy (HDCBRT) and conventional dose radiotherapy (CRT) for newly diagnosed glioblastoma (GB). Patients treated with intensity-modulated radiation therapy for newly diagnosed GB were included. In HDCBRT, specific targets received 69, 60, and 51 Gy in 30 fractions, while 60 Gy in 30 fractions was administered with a standard radiotherapy method in CRT. Overall survival (OS) and progression-free survival (PFS) were compared using the Log-rank test, followed by multivariate Cox analysis. The inverse probability of treatment weighting (IPTW) method was also applied to each analysis. Among 102 eligible patients, 45 received HDCBRT and 57 received CRT. With a median follow-up of 16 months, the median survival times of OS and PFS were 21 and 9 months, respectively. No significant differences were observed in OS or PFS in the Kaplan-Meier analyses. In the multivariate analysis, HDCBRT correlated with improved OS (hazard ratio, 0.49; 95% confidence interval, 0.27-0.90; P = 0.021), and this result remained consistent after IPTW adjustments (P = 0.028). Conversely, dose suppression due to the proximity of normal tissues and IMRT field correlated with worse OS and PFS (P = 0.008 and 0.049, respectively). A prospective study with a stricter protocol is warranted to validate the efficacy of HDCBRT for GB.

DOI: https://doi.org/10.1038/s41598-024-60154-y