Abstract 5112: Discovery of nuclear envelope mislocalization in <i>MYC-</i>driven group 3 medulloblastoma
Bibliographic record
Abstract
Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor, comprised of four distinct molecular subgroups (WNT, SHH, Group 3, and Group 4). A subset of Group 3 MB tumors harbor focal amplifications of the MYC oncogene and are particularly prone to tumor recurrence and leptomeningeal spread which currently remains incurable. Therefore, there is an urgent need for the development of therapeutic modalities that can spare the vulnerable, developing brain while having potent antitumor efficacy against recurrent MB. Through proteomic profiling of cyclophosphamide-resistant patient-derived MYC-driven Group 3 MB cell line SU_MB002, we identified nuclear envelope (NE) proteins to be highly abundant and enriched in Group 3 MB compared to normal tissue. We discovered that LBR, an inner nuclear transmembrane protein, while present in all cells at the NE, is aberrantly presented to the cell surface in MYC-driven Group 3 MB cell lines. Immunohistochemistry analysis of LBR on MB patient tumor samples identified that positive LBR staining correlated with a significantly worse prognosis and was also identified to be enriched in recurrent tissue compared to their matched primary samples. Cell surface expression flow cytometry analysis identified highly abundant cell surface expression in all MYC-driven Group 3 MB cell lines with low to no expression in human neural stem cells and other MB subgroups. Mechanistically, high resolution microscopy of endogenously HALO-tagged LBR reveals LBR cell surface presentation to be linked to ER or ER-like vesicles that are directly trafficked to the cell surface. Transcriptomic analysis of LBR cell surface positive and negative cells identify that cell surface positivity is significantly linked to cell division and mitotic processes (cell cycle process, mitotic cell cycle process, chromosome segregation, cell division, nuclear division). LBR mislocalization stems from mitosis at the time of nuclear envelope dissolution and is enriched in the hyperproliferative, therapy-resistant subpopulation of MB cells following exposure to chemotherapy and radiation in vitro and in vivo and may act as a marker for the brain tumor initiating cells that seed recurrence. Therefore, we demonstrate that LBR is an ideal therapeutic target for patients facing relapsed or treatment-refractory MB and have generated single domain antibodies in an effort to engineer LBR-specific CAR T cells. The development of therapies against NE proteins like LBR may provide patients a novel therapeutic opportunity that may be able to treat therapy-resistant, hyperproliferative MYC-driven Group 3 MB cells. Citation Format: Yujin Suk, Jorge Ibañez-Vega, Iqra Chaudhry, Martin Rossotti, Minomi Subapanditha, Petar Miletic, Stefan Custers, Laura Escudero, Alberto Delaidelli, Takuma Nakashima, Yuxi Xiao, Jason Moffat, Hiromichi Suzuki, Poul Sorensen, Kevin Henry, Chitra Venugopal, Giedre Krenciute, Sheila Singh. Discovery of nuclear envelope mislocalization in MYC-driven group 3 medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5112.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".