Biology subjects

Mak, E.

Publications and source records attributed to Mak, E..

4 recordsLinked to original sources

bioRxiv2026

Medulloblastoma Forms Symbiotic Metabolic Partnerships with Macrophages to Establish Leptomeningeal Metastases

Leptomeningeal metastases are the primary source of morbidity and mortality for pediatric medulloblastoma patients. Due to limited surgical sampling of metastases in patients, little is understood of the mechanisms of metastasis. Here, we identify biologically distinct quiescent small metastases (designated as micrometastases) and mitotically active larger metastases (macrometastases). Macrometastases are more metabolically active than micrometastases and contain higher levels of lipids, particularly cholesterol. Macrometastases secrete CXCL12, which attracts lipid-laden macrophages into the tumor. Lipid-laden macrophages upregulate the cholesterol transporter ABCG1, promoting the efflux of free cholesterol, which is then taken up by tumor cells via the HDL receptor SCARB1. CXCL12-driven macrophage recruitment and exogenous cholesterol are sufficient and necessary to drive progression of medulloblastoma leptomeningeal metastases in vivo. High fat diets drive metastatic progression in vivo. Dietary or pharmacological interventions targeting the CXCL12-SCARB1-cholesterol axis represent therapeutic strategies to either prevent or treat medulloblastoma leptomeningeal metastases.

cancer biology↗

bioRxiv2025

BRCA1 is a molecular correlate of cell proliferation in human brain development and in Group 3 and 4 medulloblastoma

The role of the BRCA1-mediated DNA damage repair pathway in regulating human brain development remains unknown, although it has been studied in mouse development. We report evidence for breast cancer type 1 susceptibility protein (BRCA1) being a molecular correlate of proliferation in human neural progenitor cells and in medulloblastoma (MB), a malignant pediatric hindbrain cancer whose cells resemble undifferentiated neural stem cells. In a computational search for molecules potentially keeping Group 3 (G3) and Group 4 (G4) MB tumour cells in a state of stalled differentiation, BRCA1 emerged as a leading candidate gene. We surveyed four independent transcriptomic datasets collectively spanning 142 human developing brain samples, multiple brain regions, and over 1.7 million single cells, and found that BRCA1 transcription is consistently enriched in human neural stem and progenitor cells, relative to differentiating or mature neurons. Across the human lifespan, BRCA1 expression is enriched in the brain during early development, particularly the first trimester of gestation. By analyzing 714 tumours, the largest transcriptomic survey of MB tumours to date, we found that BRCA1 expression is increased in carriers of isochromosome 17q (i17q) aberrations and in G4 MB tumours. Increased BRCA1 expression is associated with worse prognosis in G3 and G4 MB. In the developing cerebellum as well as in the cancer context, BRCA1 expression is correlated with transcription of the cell cycle and DNA damage repair pathways. When considered with previous mouse studies, our work is consistent with a model in which BRCA1 promotes genome surveillance in neural progenitors during human brain development and in G3 and G4 MB tumour growth, thus supporting proliferation.

genomics↗

bioRxiv2019

Correlation Of Microglial Activation With White Matter Changes In Dementia With Lewy Bodies

Dementia with Lewy bodies (DLB) is the second-leading degenerative dementia after Alzheimers disase. Neuropathologically, it is characterized by alpha-synuclein protein deposition with variable degree of concurrent Alzheimer pathology. Neuroinflammation is increasingly recognized as a significant contributor of degeneration.\n\nObjectiveto examine the relationship between microglial activation as measured with [11C]-PK11195 brain PET and MR diffusion tensor imaging (DTI) in DLB.\n\nMethodsnineteen clinically probable DLB and 20 similarly aged controls underwent structural MRI with T1-weighted and 3T DTI sequences. Eighteen DLB subjects also underwent [11C]-PK11195 PET imaging. Tract-Based Spatial Statistics (TBSS) were performed to compare DTI parameters in DLB relative to controls and identify associations of [11C]-PK11195 binding with white matter integrity.\n\nResultsTBSS showed widespread changes in all DTI parameters in the DLB group compared to controls (Threshold Free Cluster Enhancement (TFCE) p < 0.05). [11C]-PK11195 binding in parietal cortices also correlated with widespread lower mean and radial diffusivity (TFCE p < 0.05).\n\nConclusionOur study demonstrates that higher PK11195 binding is associated with a relative preservation of white matter, positioning neuroinflammation as a potential early marker in the DLB pathogenic cascade.

neuroscience↗

bioRxiv2017

Structural covariance networks in children with autism or ADHD

While autism and attention-deficit/hyperactivity disorder (ADHD) are considered distinct conditions from a diagnostic perspective, they share some phenotypic features and have high comorbidity. Taking a dual-condition approach might help elucidate shared and distinct neural characteristics.\n\nGraph theory was used to analyse properties of cortical thickness structural covariance networks across both conditions and relative to a neurotypical (NT; n=87) group using data from the ABIDE (autism; n=62) and ADHD-200 datasets (ADHD; n=69). This was analysed in a theoretical framework examining potential differences in long and short range connectivity.\n\nWe found convergence between autism and ADHD, where both conditions show an overall decrease in CT covariance with increased Euclidean distance compared to a neurotypical population. The two conditions also show divergence: less modular overlap between the two conditions than there is between each condition and the neurotypical group. Lastly, the ADHD group also showed reduced wiring costs compared to the autism groups.\n\nOur results indicate a need for taking an integrated approach when considering highly comorbid conditions such as autism and ADHD. Both groups show a distance-covariance relation that more strongly favours short-range over long-range. Thus, on some network features the groups seem to converge, yet on others there is divergence.

neuroscience↗