Citations

Abstract Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 (G3) MBs have poor overall survival at < 50%, higher frequency of metastasis, and no targeted therapies. Amplification of MYC and activation of TGFβ signaling are frequent in G3MB. Remarkably, some tumors have no reported mutations, suggesting roles for epigenetic mechanisms in driving disease. We have generated novel humanized models for G3MB by transducing neuroepithelial stem cells (NESC) derived from human induced pluripotent stem (iPSC) cells with TGFβ effectors alone and/or in combination with MYC, prioritizing combinations observed in patients. We determined that both MYC and TGFβ effectors drove tumor formation in vivo with the combination driving more aggressive tumors and higher frequency of metastasis. NESC-derived tumors clustered with human G3/G4MB, indicating our models recapitulated human disease. To decipher mechanisms of resistance, we integrated CUT&RUN for MYC genomic localization and histone PTMs with RNA-sequencing and discovered MYC-bound neural developmental genes repressed in MYC and TGFβR1-driven lines. Further interrogation identified JARID1B, a MYC binding partner, as a regulator of many of these repressed neural genes. We postulate that deregulation of MYC and context-specific targeting to the chromatin template culminates in transcriptional alterations that promote aggressive G3MB. To further investigating therapeutic vulnerabilities, we have performed a in vivo whole genome CRISPRi screen to reveal important drivers of malignancy, one of the first of it’s kind in brain tumors. We are functionally validating key candidate sgRNAs that were differentially significant in primary tumors and may also have key roles in driving metastasis. Excitingly, many sgRNAs identified from the screen were chromatin modifiers and may be important co-factors of MYC-mediated regulation on the epigenome. Collectively, our studies provide a critical framework for understanding mechanisms of resistance and the epigenetic landscape of MYC- and TGFβ-driven MB.

Abstract One of the most significant unmet clinical challenges in paediatric oncology is the development of novel therapeutic strategies for recurrent medulloblastoma (R-MB). MYC-driven MBs are defined as classically cold tumours with a low incidence of infiltrating immune cells, resulting in a therapeutic challenge. The identification of cell-cell interactions between tumour and immune cells may provide insight into critical intercellular communications and manipulations occurring within the tumour immune microenvironment (TME). We hypothesised that the key cell-cell interactions in MYC-driven primary and recurrent MB may reveal dominant immune-suppressive mechanisms and uncover targetable therapeutic vulnerabilities. Paired primary-recurrent bulk RNA-sequencing data, confirmed myeloid cells as the most infiltrating immune cell type in group3-MB and group4-MB. Comprehensive spatial phenotypic and cell-cell communication analyses corroborated this discovery, validating an increased incidence of macrophages in the matched-recurrent tumours. Subsequently, we used innovative algorithms for 10X MB single-cell data to predict interactions between tumour-cell ligands and immune-cell receptors within the TME; macrophages emerged as the core immune-cells involved in interactions throughout the TMEs, with the most significant ligand-receptor interaction and inflammatory response between MIF and CD74. In-depth immunohistochemistry analyses of primary and recurrent group3 and group4 tumours, and exhaustive tissue microarrays demonstrated expression of both CD74 and MIF, with limited expression of CD74 within the brain. To investigate the therapeutic potential of CD74, we developed recurrent, immune competent MYC-driven medulloblastoma mouse models. Comprehensive deconvolution analysis confirmed the TME integrity of our models to mirror that of the human disease. Locoregional delivery and repeat dosing of a bioactive-CD74 peptide demonstrated complete tumour clearance in our immune-competent mouse models of primary and recurrent MB, demonstrating the significant therapeutic potential of targeting the CD74-MIF axis in MYC-driven primary and recurrent MB. Key cellular interactions and therapeutic vulnerabilities within the tumour microenvironment of MYC-driven medulloblastoma (MB) have been identified, highlighting the CD74-MIF axis as a target for next-generation immunotherapies.

Abstract Platinum-based chemotherapy remains a cornerstone of treatment for triple-negative breast cancer (TNBC), yet the molecular determinants governing platinum response remain poorly defined. By leveraging the randomized Phase II INFORM trial, which compared neoadjuvant cisplatin to anthracycline-based therapy in BRCA1/2 -mutant breast cancer—we identified miR-362-3p as a specific regulator of cisplatin sensitivity. Higher plasma miR-362-3p expression was exclusively associated with favorable clinical outcome in the cisplatin arm, with no association observed in the AC arm, decoupling platinum-specific vulnerability from general chemotherapy response. We used gain- and loss-of-function TNBC models to establish that miR-362-3p functions as a potent sensitizer to cisplatin in vitro and in vivo . Integrated TCGA analysis and experimental validation identified BCLAF1, a key regulator of DNA damage response, as a direct repression target of miR-362-3p. We uncovered a novel role for the miR-362-3p/ BCLAF1 axis in overcoming platinum resistance in TNBC.

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) arises predominantly from activating KRAS mutations, yet individual genetic variants differ markedly in signaling output and clinical impact. G12D, the most prevalent variant, strongly drives oncogenic programs, whereas G12R signals less efficiently through the AKT and ERK pathways and is associated with longer patient survival than G12D-driven PDAC. Methods: To elucidate how these differences influence early cellular transformation, we expressed a panel of KRAS mutants in non-cancerous pancreatic ductal epithelial cells as a model of early PDAC initiation and profiled transcriptional and phospho-proteomic responses. We next examined whether epigenetic differences translate into mutation-specific changes in nuclear organization using quantitative imaging of G12D- and G12R-expressing nuclei at 24 and 48 h. Results: Each variant established a unique regulatory program enriched for chromatin remodelers, histone modifiers, and nuclear structural factors, indicating that variant-specific KRAS signaling rapidly develops divergent epigenetic states. Integrated transcriptomic and phospho-proteomic analyses identified G12D and G12R as the most divergent variants. G12D induced pronounced nuclear remodeling, including increased nuclear size, irregular morphology, and reorganization of the nucleolus and spliceosome, consistent with extensive chromatin and transcriptional reprogramming. In contrast, G12R elicited a weaker response, with minimal or delayed structural changes. Conclusions: Together, these findings demonstrate that KRAS mutational context in pancreatic ductal epithelial cells shapes early transcriptional reprogramming that actively remodels nuclear architecture and nuclear sub-compartments. This work establishes nuclear structural remodeling as a structural state of KRAS-driven epigenetic dysregulation during PDAC initiation.

Objective: To survey critical areas of variation in published research methodology with a primary aim of highlighting fundamental aspects that contribute to ongoing controversy surrounding optimal management of patients with sporadic vestibular schwannoma. Interventions: Observation, stereotactic radiosurgery (SRS), and microsurgery. Main outcome measures: Variation in reported outcomes surrounding facial function, useful hearing, tumor pseudoprogression following SRS, and tumor growth/natural history. Results: Published research defines “good” post-treatment facial function as anything ranging from HB I, ≤HB II, to ≤HB III. While most studies define serviceable hearing as AAO Class A/B, others include Class C in published post-treatment hearing preservation results; meanwhile, patients report their greatest decrement in quality-of-life at a threshold around 75% in word recognition scores. Heterogeneously defined as post-SRS tumor growth 6 months after SRS to 5 years after SRS, the reported incidence of tumor pseudoprogression ranges from 7% to 77% within the published literature. Natural history studies that employ linear tumor measurements consistently suggest most tumors do not grow following diagnosis, whereas volumetric studies of natural history suggest the exact opposite is true. Limited follow-up and absent time-to-event analyses undermine many outcomes surrounding vestibular schwannoma that are inherently time-dependent. Conclusions: Disparate definitions used in vestibular schwannoma research beget variable outcome reporting and confuse interpretation of optimal management, particularly for the increasingly common scenario of a small tumor in a minimally symptomatic patient. Progress towards optimizing management requires re-evaluation and alignment on key outcome measures to improve consistency in reporting with renewed emphasis on clinically significant, patient-driven outcomes that often exceed the thresholds most frequently studied to date.

While the clinical focus on the sentinel lymph node biopsy (SLNB) is the presence of intra- or extra-nodal metastases, preclinical studies suggest that tumor-draining SLNB-associated vascular architecture and adhesion properties are altered regardless of SLNB positivity. Human intravital microscopy (HIVM) has defined blood vessel abnormalities that may impact lymphocyte adhesion and systemic drug delivery at primary melanoma sites. In this pilot study of HIVM during melanoma SLNB, we sought to determine the feasibility of obtaining HIVM observations of SLNB-associated vessels. We successfully performed HIVM in all 20 SLNB patients, and 7 were found to have nodal micrometastases by standard pathology. HIVM was capable of identifying both functional and non-functional SLNB-associated vessels based on the presence or absence of fluorescent dye uptake, respectively. Comparing vessel characteristics as a secondary exploratory objective, no statistically significant differences were noted in the diameter, flow rate, functionality, or shear stress of SLNB-associated blood vessels between positive and negative SLNBs, which may likely have been a reflection of the minimal disease burden. Nonetheless, these initial observations provide the framework to optimize future trials of HIVM in cancer patients.

Abstract Background XK disease is a multisystem neurodegenerative disorder caused by mutations in the XK gene that codes for the lipid scramblase XK. Objective The aim was to describe the lipidomic spectrum in postmortem brain tissue from XK patients. Methods We measured the levels of 593 lipid species in the caudate nucleus (CN), putamen, and dorsolateral prefrontal cortex (DLPFC) from postmortem tissues of 5 XK patients and 6 controls. Results In XK patients, we observed increased levels of triacylglycerol, monoacylglycerol, phosphatidylserine, and ceramide in the CN. Acylated phosphatidylglycerol levels were reduced in both the CN and putamen. Acyl carnitine, dihydrosphingomyelin, and monosialodihexosylganglioside were reduced, whereas N ‐acyl phosphatidylethanolamine was increased in the DLPFC. N ‐Acyl serine was reduced in all three regions. Conclusions Our findings provide initial evidence of abnormal sphingolipid and phospholipid concentrations in the brains of XK patients and may provide insights into mechanisms of neurodegeneration in this disease. © 2026 International Parkinson and Movement Disorder Society.