bims-malgli 2024-12-22 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2024–12–22
fourteen papers selected by
Oltea Sampetrean, Keio University

Nose-to-Brain Delivery of Biomimetic Nanoparticles for Glioblastoma Targeted Therapy.
Emergence of the cell-matrix adhesion element ILK as a player in glioblastoma cell plasticity.
A novel nuclear RNA HSD52 scaffolding NONO/SFPQ complex modulates DNA damage repair to facilitate temozolomide resistance.
Metabolic checkpoints in glioblastomas: targets for new therapies and non-invasive detection.
Enhanced Antiglioma Effect by a Vitamin D3-Inserted Lipid Hybrid Neutrophil Membrane Biomimetic Multimodal Nanoplatform.
Intraoperative superb microvascular ultrasound imaging in glioma: novel quantitative analysis correlates with tumour grade.
Life-style and metabolic factors do not affect risk for glioma: a prospective population-based study (The Cohort of Norway).
Radiographic and visual response to the type II RAF inhibitor tovorafenib in children with relapsed/refractory optic pathway glioma in the FIREFLY-1 trial.
Radiological, clinical, and molecular analyses reveal distinct subtypes of butterfly glioblastomas affecting the prognosis.
Magnesium-Phenolic Nanoeditor Refining Gliomatous T Cells for Metalloimmunotherapy.
Give me a sign(ature): Converging on the CSC of glioblastoma.
Real life data of ONC201 (dordaviprone) in pediatric and adult H3K27-altered recurrent diffuse midline glioma: Results of an international academia-driven compassionate use program.
Solid stress estimations via intraoperative 3D navigation in patients with brain tumors.
Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening.

ACS Appl Mater Interfaces. 2024 Dec 18.

Nose-to-Brain Delivery of Biomimetic Nanoparticles for Glioblastoma Targeted Therapy.

Natália Noronha Ferreira, Celisnolia Morais Leite, Natália Sanchez Moreno, Renata Rank Miranda, Paula Maria Pincela Lins, Camila Fernanda Rodero, Edilson de Oliveira Junior, Eliana Martins Lima, Rui M Reis, Valtencir Zucolotto.

  Glioblastoma (GBM) is an extremely aggressive form of brain cancer that remains challenging to treat, especially owing to the lack of effective targeting and drug delivery concerns. Due to its anatomical advantages, the nose-to-brain strategy is an interesting route for drug delivery. Nanoengineering has provided technological tools and innovative strategies to overcome biotechnological limitations, which is promising for improving the effectiveness of conventional therapies. Herein, we designed a biomimetic multifunctional nanostructure produced by polymeric poly(d,l-lactic-co-glycolic) acid (PLGA) core loaded with Temozolomide (TMZ) coated with cell membrane isolated from glioma cancer cells. The developed nanostructures (NP-MB) were fully characterized, and their biological performance was investigated extensively. The results indicate that NP-MB could control TMZ release and promote TMZ permeation in the ex vivo nasal porcine mucosa. The higher cytotoxicity of NP-MB in different glioma cell lines, particularly against U251 cells, reinforces their potential for homotypic targeting. The chicken chorioallantoic membrane assay revealed a tumor size reduction and antiangiogenic activity. In vivo biodistribution studies showed that NP-MB effectively reaches the brain following nasal administration. These findings suggest that NP-MB holds promise as a biomimetic nanoplatform for effective targeting and homotypic recognition in GBM therapy with high potential for clinical translation.

Keywords:  PLGA-based nanoparticles; Temozolomide; biomimetic delivery systems; glioblastoma treatment; homotypic recognition; nanotechnology; nose-to-brain delivery

DOI:  https://doi.org/10.1021/acsami.4c16837
Dev Cell. 2024 Dec 16. pii: S1534-5807(24)00694-4. [Epub ahead of print]59(24): 3189-3190

Emergence of the cell-matrix adhesion element ILK as a player in glioblastoma cell plasticity.

Marie-Pierre Junier, Elias A El-Habr.

Glioblastoma cells exhibit remarkable plasticity, enabling them to adapt to environmental cues and transition through various developmental-like states with distinct properties. In this issue of Developmental Cell, Loftus et al. identify ILK as an intrinsic regulator of glioblastoma cell transitions between progenitor-like and mesenchymal/astrocyte-like states.

DOI: https://doi.org/10.1016/j.devcel.2024.11.012
Neuro Oncol. 2024 Dec 14. pii: noae272. [Epub ahead of print]

A novel nuclear RNA HSD52 scaffolding NONO/SFPQ complex modulates DNA damage repair to facilitate temozolomide resistance.

Nan Sun, Qun Chen, Hao Chen, Penggang Sun, Yuxiang Liu, Dan Song, Daohan Yu, Pandeng Wang, Yu Song, Jie Qin, Kaifu Tian, Junzhe Zhong, Wenbin Ma, Hanwen Xuan, Da Qian, Ye Yuan, Tongzheng Chen, Xin Wang, Chuanlu Jiang, Jinquan Cai, Xiangqi Meng.

   BACKGROUND: Temozolomide (TMZ) is used in the treatment of glioblastoma (GBM). However, the primary obstacle remains the emergence of TMZ chemotherapy resistance. NONO and SFPQ are multifunctional nuclear proteins involved in genome stability and gene regulation. However, the specific role of NONO and SFPQ in TMZ resistance of GBM remains to be explored.
METHODS: RIP-chip and RNA microarray of TMZ-resistant and parental cells were performed for the gain of HSD52. The effects of HSD52 on TMZ resistance were investigated through in vitro assays, intracranial xenograft and GBM organoid models. The underlying mechanisms were explored by DNA methylation chip, RIP, RNA pulldown assays, among others. GBM clinical samples were rolled in to investigate the clinical significance of HSD52.
RESULTS: We identified a novel non-coding RNA, HSD52, that was highly expressed in TMZ-resistant GBM and facilitated the interaction between NONO and SFPQ. H3 ubiquitination attenuation and reduced DNMT1 recruitment increased HSD52 transcription via DNA hypo-methylation. HSD52 formed an RNA duplex with UFL1 mRNA, thereby promoting NONO/SFPQ complex binding to UFL1 mRNA and enhancing its stability, and then contributed to TMZ resistance through activating ATM signaling pathway. In vivo xenograft and GBM organoid models showed significant repression in tumor growth after HSD52 knockout with TMZ treatment. In GBM clinical samples, HSD52 was responsible for the malignant progression and TMZ resistance.
CONCLUSIONS: Our results revealed that HSD52 could serve as a promising therapeutic target to overcome TMZ resistance, improving the clinical efficacy of TMZ chemotherapy in GBM.

Keywords:  DNA damage repair; Glioblastoma; HSD52; NONO/SFPQ complex; Temozolomide resistance

DOI:  https://doi.org/10.1093/neuonc/noae272
Front Oncol. 2024 ;14 1462424

Metabolic checkpoints in glioblastomas: targets for new therapies and non-invasive detection.

Wenhao Li, Zhihao Wang, Siliang Chen, Mingrong Zuo, Yufan Xiang, Yunbo Yuan, Yuze He, Shuxin Zhang, Yanhui Liu.

  Glioblastoma (GBM) is a highly malignant tumor of the central nervous system that remains intractable despite advancements in current tumor treatment modalities, including immunotherapy. In recent years, metabolic checkpoints (aberrant metabolic pathways underlying the immunosuppressive tumor microenvironment) have gained attention as promising therapeutic targets and sensitive biomarkers across various cancers. Here, we briefly review the existing understanding of tumor metabolic checkpoints and their implications in the biology and management of GBM. Additionally, we discuss techniques that could evaluate metabolic checkpoints of GBM non-invasively, thereby potentially facilitating neo-adjuvant treatment and dynamic surveillance.

Keywords:  glioblastoma; immunotherapy; liquid biopsy; metabolic checkpoints; multimodal MRI

DOI:  https://doi.org/10.3389/fonc.2024.1462424
ACS Nano. 2024 Dec 18.

Enhanced Antiglioma Effect by a Vitamin D3-Inserted Lipid Hybrid Neutrophil Membrane Biomimetic Multimodal Nanoplatform.

Weichong He, Wei Lv, Linfeng Liu, Yue Gong, Kefan Song, Jiangna Xu, Wei Zhao, Shengnan Li, Zhiyi Min, Qinhua Chen, Jiaqing Yin, Yuqin Chen, Hufeng Fang, Hongliang Xin, Xiangming Fang.

  Glioblastoma, the most prevalent malignant brain tumor, is a lethal threat to human health, with aggressive and infiltrative growth characteristics that compromise the clinical treatment. Herein, we developed a vitamin D3-inserted lipid hybrid neutrophil membrane biomimetic multimodal nanoplatform (designated as NED@MnO2-DOX) through doxorubicin (DOX)-loaded manganese dioxide nanoparticles (MnO2) which were coated with a vitamin D3-inserted lipid hybrid neutrophil membrane. It was demonstrated that in addition to chemotherapy and chemo-dynamic therapy efficacy, NED@MnO2-DOX exhibited great power to activate and amplify immune responses related to the cGAS STING pathway, bolstering the secretion of type I interferon-β and proinflammatory cytokines, promoting the maturation of DC cells and infiltration of CD8+T cells into the glioma tissue, thereby reversing the immunosuppressive microenvironment of glioma from a "cold" tumor to a "hot" tumor. The biomimetic multimodal nanoplatform has potential as a multimodal strategy for glioma-targeted treatment, especially holding considerable promise for the development of innate immune therapy for glioma.

Keywords:  biomimetic; cGAS-STING signaling pathway; drug delivery; glioblastoma; multimodal immunotherapy

DOI:  https://doi.org/10.1021/acsnano.4c13470
medRxiv. 2024 Dec 08. pii: 2024.12.07.24318636. [Epub ahead of print]

Intraoperative superb microvascular ultrasound imaging in glioma: novel quantitative analysis correlates with tumour grade.

Luke Dixon, Alistair Weld, Dolin Bhagawati, Neekhil Patel, Stamatia Giannarou, Matthew Grech-Sollars, Adrian Lim, Sophie Camp.

Accurate grading of gliomas is critical to guide therapy and predict prognosis. The presence of microvascular proliferation is a hallmark feature of high grade gliomas which traditionally requires targeted surgical biopsy of representative tissue. Superb microvascular imaging (SMI) is a novel high resolution Doppler ultrasound technique which can uniquely define the microvascular architecture of whole tumours. We examined both qualitative and quantitative vascular features of gliomas captured with SMI, analysing flow signal density, vessel number, branching points, curvature, vessel angle deviation, fractal dimension, and entropy. Results indicate that high-grade gliomas exhibit significantly greater vascular complexity and disorganisation, with increased fractal dimension and entropy, correlating with known histopathological markers of aggressive angiogenesis. The integrated ROC model achieved high accuracy (AUC = 0.95), highlighting SMI's potential as a non-invasive diagnostic and prognostic tool. While further validation with larger datasets is required, this study opens avenues for SMI in glioma management, supporting intraoperative decision-making and informing future prognosis.

DOI: https://doi.org/10.1101/2024.12.07.24318636
Front Oncol. 2024 ;14 1471733

Life-style and metabolic factors do not affect risk for glioma: a prospective population-based study (The Cohort of Norway).

Anamaria Gheorghiu, Cathrine Brunborg, Tom B Johannesen, Eirik Helseth, John-Anker Zwart, Markus K H Wiedmann.

   Background: The identification of modifiable risk factors for intracranial glioma remains a significant challenge. While lifestyle factors and metabolic syndrome are well-established risk factors for various other cancers, their association with glioma risk remains unclear.
Objectives: This study aims to conduct a comprehensive analysis of lifestyle factors and metabolic factors in relation to glioma risk.
Methods: The Cohort of Norway (CONOR) is a prospective, population-based health survey encompassing anthropometric measurements, blood tests and health questionnaires. CONOR data were linked to the National Cancer Registry to identify incident glioma cases. Follow-up time was calculated in person-years from the baseline examination until the date of glioma diagnosis, death, or the end of the follow-up period. Cox proportional hazards regression was used to calculate hazard ratios (HR).
Results: The study cohort included 160,938 women and men. Over 2.8 million person-years of follow-up, 319 intracranial gliomas were diagnosed. Lifestyle factors such as physical activity, alcohol consumption, smoking, and marital status were not associated with glioma risk. There was no increased glioma risk among participants with diabetes mellitus or hypertension. Furthermore, metabolic syndrome in both women and men was not associated with an elevated risk of glioma. Blood lipids, including total cholesterol, triglycerides, and HDL, were not linked to glioma risk. However, increasing LDL levels were associated with a decreased risk of glioma in men (HR per category 0.84; 95% CI 0.74-0.96), but not in women.
Conclusion: This is the first comprehensive prospective cohort study to evaluate potentially modifiable risk factors for glioma. Our findings do not support previously suggested associations between smoking, alcohol consumption, or metabolic syndrome and glioma risk.

Keywords:  brain tumor; diabetes; glioblastoma; glioma; metabolic syndrome; obesity; risk factor; smoking

DOI:  https://doi.org/10.3389/fonc.2024.1471733
Neuro Oncol. 2024 Dec 19. pii: noae274. [Epub ahead of print]

Radiographic and visual response to the type II RAF inhibitor tovorafenib in children with relapsed/refractory optic pathway glioma in the FIREFLY-1 trial.

Karsten Nysom, Lindsay B Kilburn, Sarah E S Leary, Daniel B Landi, Evelien de Vos-Kerkhof, Sébastien Perreault, Olaf Witt, David S Ziegler, Pablo Hernáiz Driever, Andrea T Franson, Patricia A Baxter, Nicholas S Whipple, Cassie Kline, Devorah Segal, Nada Jabado, Simon Bailey, Geoffrey McCowage, Jordan R Hansford, Dong-Anh Khuong-Quang, Nicholas G Gottardo, Timothy Hassall, Jung Woo Han, Michal Yalon Oren, Susan N Chi, Jiaheng Qiu, Daniel Da Costa, Sandya Govinda Raju, Peter Manley, Darren Hargrave.

   BACKGROUND: Due to their anatomical locations, optic pathway gliomas (OPGs) can rarely be cured by resection. Given the importance of preserving visual function, we analyzed radiological and visual acuity (VA) outcomes for the type II RAF inhibitor tovorafenib in the OPG subgroup of the phase 2 FIREFLY-1 trial.
METHODS: FIREFLY-1 investigated the efficacy (arm 1, n=77), safety, and tolerability (arms 1/2) of tovorafenib (420 mg/m2 once weekly; 600 mg maximum) in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma (pLGG). In this post hoc analysis, anti-tumor activity and VA were analyzed in arm 1 patients with OPG. Anti-tumor activity was independently assessed per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG), Response Assessment in Pediatric Neuro-Oncology-LGG (RAPNO) and RANO-LGG criteria. The data cutoff was June 5, 2023.
RESULTS: Forty-two of 77 patients had OPGs; 35 of 42 had ≥2 VA assessments. The overall response rate in the OPG subgroup according to RANO-HGG, RAPNO and RANO-LGG criteria were 64%, 50%, and 55%, with clinical benefit rates 95%, 88%, and 90%, respectively. VA per patient was preserved for 80% of patients; 31% demonstrated improved VA; VA per eye was preserved in 87%, with 27% improving. The safety profile in the arm 1 OPG subgroup was similar to the overall FIREFLY-1 safety analysis set.
CONCLUSIONS: Tovorafenib demonstrated anti-tumor activity in relapsed/refractory BRAF-altered OPG across radiological assessment criteria and was generally well tolerated. Importantly, vision remained stable or improved in most patients.

Keywords:  BRAF; FIREFLY-1; optic pathway glioma; tovorafenib; visual acuity

DOI:  https://doi.org/10.1093/neuonc/noae274
Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae180

Radiological, clinical, and molecular analyses reveal distinct subtypes of butterfly glioblastomas affecting the prognosis.

Ichiyo Shibahara, Ryota Shigeeda, Takashi Watanabe, Yasushi Orihashi, Yoko Tanihata, Kazuko Fujitani, Hajime Handa, Yuri Hyakutake, Mariko Toyoda, Madoka Inukai, Kohei Uemasu, Mitsuhiro Shinoda, Hideto Komai, Sumito Sato, Takuichiro Hide, Toshihiro Kumabe.

   Background: Glioblastoma (GB) is known for its highly invasive nature. Images of butterfly GB (bGB) often illustrate this characteristic, but the molecular background and origins of bGB remain unknown.
Methods: We analyzed a cohort of 34 bGB patients from our dataset (K-cohort) and 46 bGB patients from publicly available datasets, including TCGA-GBM, CPTAC-GBM, IvyGAP, and UPENN-GBM.
Results: In the K-cohort, the median age was 66 years, and molecular analyses revealed TERT promoter mutations in 55.9% of cases, with no cases exhibiting H3F3A, HIST1H3B, or BRAF mutations. Sequential radiological imaging from the K-cohort provided unique insights, showing one case originating in the corpus callosum (CC) and 3 cases originating in the cerebral hemisphere before developing into bGB. Multi-regional sampling supported a mutational trajectory from the hemisphere to the CC. These observations indicate the presence of 2 distinct radiological origins for bGB. Consequently, we classified cases into CC-type and Hemispheric-type based on the tumor volume ratio within the CC. This subgrouping was clinically meaningful; the CC-type is an independent poor prognostic factor for overall survival, with a hazard ratio of 1.8 (95% confidence interval 1.1-3.0, P = .033), and is molecularly distinct by a higher frequency of methylated MGMTp (P = .0039) compared to the Hemispheric-type.
Conclusions: Our results highlight that the radiological features of bGB are not homogenous and can indicate 2 potential subtypes based on their origins. Further studies are mandatory, but CC-type and Hemispheric-type exhibit distinct clinical backgrounds, outcomes, and molecular features.

Keywords:  MGMT; butterfly glioblastoma; corpus callosum; surgery; survival

DOI:  https://doi.org/10.1093/noajnl/vdae180
ACS Nano. 2024 Dec 19.

Magnesium-Phenolic Nanoeditor Refining Gliomatous T Cells for Metalloimmunotherapy.

Wenxi Li, Hao Tian, Ziliang Yan, Xinying Yu, Bei Li, Yunlu Dai.

  More than the sparse infiltration in glioblastoma, cytotoxic T lymphocytes (CTLs) also function inefficiently and overexpress the inhibitory markers, especially the identified NK cell receptor (NK1.1). However, most studies solely focus on how to augment tumor-infiltrating CTLs and overlook their killing maintenance. Metalloimmunotherapy has been proven to improve the functionalities of CTLs, but it has barely adapted to glioblastoma due to the severe limitations of safe delivery and the brain's physiological properties. Herein, we synthesized an amphipathic polyethylene glycol (PEG) polymer (designated as MPP) modified with the choline analogue 2-methacryloyloxyethyl phosphorylcholine (MPC) and polyphenol moieties to customize a nanoeditor (Mg2+@MK-8931@MPP) by coordinating Mg2+ and entrapping the hydrophobic BACE1 inhibitor MK-8931, then precisely redressing the gliomatous CTL sparsity and cytotoxic dysfunction. Upon MPC-assisted local accumulation in glioblastoma, Mg2+@MK-8931@MPP nanoeditors release MK-8931 to repolarize M2-like macrophages, facilitating CTL infiltration quantitatively. The cenogenetic immune adjuvant Mg2+ ulteriorly fortifies the T-cell receptor downstream signals to enhance the functionality of the ingoing CTLs in quality, leading to the secretion of high-level antitumor cytokines and cytotoxic proteins. Further blocking the inhibitory NK1.1 on CTLs by anti-NK1.1 antibodies can extend their cytolytic endgame. Studies on T-cell-deficient and wild-type mouse models support the immunomodulating feasibility of Mg2+@MK-8931@MPP. This gliomatous CTL-tailored strategy concurrently broadens metalloimmunotherapy to glioblastoma treatment and highlights the necessity of enforcing gliomatous CTLs' functionality.

Keywords:  cytotoxic T lymphocytemodulation; glioblastoma; macrophage polarization; magnesium-phenolic coordination; metalloimmunotherapy

DOI:  https://doi.org/10.1021/acsnano.4c13388
Neuron. 2024 Dec 18. pii: S0896-6273(24)00837-7. [Epub ahead of print]112(24): 3987-3988

Give me a sign(ature): Converging on the CSC of glioblastoma.

Kunal S Patel, Lindsey Dudley, Harley I Kornblum.

The identification of stem cells in glioblastomas has been controversial. In this issue of Neuron, Xie et al.1 establish gene signatures for cellular states and a quiescent cancer stem cell (qCSC) and demonstrate that the qCSC population expands in recurrence.

DOI: https://doi.org/10.1016/j.neuron.2024.11.012
Eur J Cancer. 2024 Dec 11. pii: S0959-8049(24)01772-6. [Epub ahead of print]216 115165

Real life data of ONC201 (dordaviprone) in pediatric and adult H3K27-altered recurrent diffuse midline glioma: Results of an international academia-driven compassionate use program.

D Di Carlo, M Annereau, M Vignes, L Denis, N Epaillard, S Dumont, D Guyon, A Rieutord, S Jacobs, V Salomon, I Yoldjian, F Duperray, L Brunel, X Baiao, F Lemos, E Vauleon, M Capra, S Abbou, M Touat, M Sanson, V Gandemer, E De Carli, F Bourdeaut, I Hezam, G Vassal, J Grill.

   INTRODUCTION: H3K27-altered diffuse midline gliomas (DMG) have limited therapeutic options and a very poor prognosis. Encouraging responses were observed in early clinical trials with ONC201. As ONC201 was unavailable in Europe, a compassionate use program supported by the French Authorities was launched for patients at progression after standard of care radiotherapy.
METHODS: This program was developed by the French Society of Pediatric Oncology (SFCE) and Association des Neuro-Oncologues d'Expression Française in collaboration with the French National Agency For Medicines and Health Products Safety and Parents Associations.
RESULTS: 174 patients (102 children, 72 adults) from 14 countries were treated from November 2021 to August 2023 at Gustave Roussy Institut (Villejuif, France). 37 % received a second course of irradiation at the time of relapse. Median duration of treatment was 57 days or 1,9 months (mo) (range 1-456 days). Median OS since diagnosis for the whole cohort was 466 days or 15,5 mo (112-2612 days); 426 or 14,2 mo (112-2612 days) and 590 or 19,6 mo (range 160-1881) for children and adults, respectively (p = 0.001). Median OS after ONC201 start was 143 days or 4,7 mo (1-711 days) for the whole cohort. Univariate and multivariable analysis identified site (thalamus) and age (older) as favorable prognostic factors. Reirradiation was associated with significantly longer survival after ONC201 start only in children.
CONCLUSION: While the efficacy of ONC201 needs validation in a controlled randomized clinical trial, our real-life data support a better outcome for patients with thalamic tumors treated with ONC201. We demonstrated furthermore the feasibility of a successful academia-driven compassionate use program.

Keywords:  Adults; Children; DIPG; H3K27M; ONC201; Thalamus

DOI:  https://doi.org/10.1016/j.ejca.2024.115165
medRxiv. 2024 Dec 04. pii: 2024.11.28.24318104. [Epub ahead of print]

Solid stress estimations via intraoperative 3D navigation in patients with brain tumors.

Hadi T Nia, Meenal Datta, Ashwin S Kumar, Saeed Siri, Gino B Ferraro, Sampurna Chatterjee, Jeffrey M McHugh, Patrick R Ng, Timothy R West, Otto Rapalino, Bryan D Choi, Brian V Nahed, Lance L Munn, Rakesh K Jain.

Background: Physical forces exerted by expanding brain tumors - specifically the compressive stresses propagated through solid tissue structures - reduces brain perfusion and neurological function, but heretofore has not been directly measured in patients in vivo . Solid stress levels estimated from tumor growth patterns are negatively correlated with neurological performance in patients. We hypothesize that measurements of solid stress can be used to inform clinical management of brain tumors.
Methods: We developed an intraoperative technique to quantitatively estimate solid stress and brain replacement by the tumor. In 30 patients we made topographic measurements of brain deformation through the craniotomy site with a neuronavigation system during surgical workflows immediately preceding tumor resection (< 5 minutes in the OR). Utilizing these measurements in conjunction with finite element modeling, we calculated solid stress within the tumor and the brain, and estimated the amount of brain tissue replaced, i.e., lost, by the tumor growth.
Results: Mean solid stresses were in the range of 10 to 600 Pa, and the amount of tissue replacement was up to 10% of the brain. Brain tissue loss in patients delineated glioblastoma from brain metastatic tumors, and in mice solid stress was a sensitive biomarker of chemotherapy response.
Conclusions: We present here a quantitative approach to intraoperatively measure solid stress in patients that can be readily adopted into standard clinical workflows. Brain tissue loss due to tumor growth is a novel mechanical-based biomarker that, in addition to solid stress, may inform personalized management in future clinical studies in brain cancer.
Key Points: Intraoperative and computational technique quantified solid stress and tissue loss in 30 patients Solid stress and tissue loss distinguished tumor types, showing potential as clinical biomarkers.
Importance of the Study: This study addresses a critical gap, as solid stress has been implicated in tumor progression and treatment resistance but not directly measured in patients with brain cancers before. Here, we present a novel intraoperative technique to quantitatively measure solid stress and brain tissue replacement in brain tumor patients. By combining intraoperative neuro-navigation with finite element modeling, we estimate solid stress and quantify the loss of brain tissue replaced by tumor growth. Importantly, higher tissue replacement was associated with glioblastoma compared to metastatic tumors. In mice, solid stress is a sensitive biomarker of treatment response. These findings establish solid stress and tissue replacement as potential physical biomarkers to inform personalized management of brain tumors. Quantifying these mechanical forces during surgery could help predict patient outcomes and guide clinical decision-making.

DOI: https://doi.org/10.1101/2024.11.28.24318104
Nat Commun. 2024 Dec 19. 15(1): 10703

Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening.

Anand Ramani, Giovanni Pasquini, Niklas J Gerkau, Vaibhav Jadhav, Omkar Suhas Vinchure, Nazlican Altinisik, Hannes Windoffer, Sarah Muller, Ina Rothenaigner, Sean Lin, Aruljothi Mariappan, Dhanasekaran Rathinam, Ali Mirsaidi, Olivier Goureau, Lucia Ricci-Vitiani, Quintino Giorgio D'Alessandris, Bernd Wollnik, Alysson Muotri, Limor Freifeld, Nathalie Jurisch-Yaksi, Roberto Pallini, Christine R Rose, Volker Busskamp, Elke Gabriel, Kamyar Hadian, Jay Gopalakrishnan.

Brain organoids offer unprecedented insights into brain development and disease modeling and hold promise for drug screening. Significant hindrances, however, are morphological and cellular heterogeneity, inter-organoid size differences, cellular stress, and poor reproducibility. Here, we describe a method that reproducibly generates thousands of organoids across multiple hiPSC lines. These High Quantity brain organoids (Hi-Q brain organoids) exhibit reproducible cytoarchitecture, cell diversity, and functionality, are free from ectopically active cellular stress pathways, and allow cryopreservation and re-culturing. Patient-derived Hi-Q brain organoids recapitulate distinct forms of developmental defects: primary microcephaly due to a mutation in CDK5RAP2 and progeria-associated defects of Cockayne syndrome. Hi-Q brain organoids displayed a reproducible invasion pattern for a given patient-derived glioma cell line. This enabled a medium-throughput drug screen to identify Selumetinib and Fulvestrant, as inhibitors of glioma invasion in vivo. Thus, the Hi-Q approach can easily be adapted to reliably harness brain organoids' application for personalized neurogenetic disease modeling and drug discovery.

DOI: https://doi.org/10.1038/s41467-024-55226-6