TMIC-02CELL AUTONOMOUS AND CELL NON-AUTONOMOUS ROLES OF p75 NEUROTROPHIN RECEPTOR (p75<sup>NTR</sup>) IN GLIOMA INVASION
Bibliographic record
Abstract
Human glioblastoma is a heterogeneous tumor composed of tumor cells and a small population known as brain tumor initiating cells (BTICs) or glioblastoma stem-like cells. BTICs appear to drive tumor progression, underlie therapeutic resistance and have been highlighted as therapeutic targets for patients with malignant glioma. The ability of glioma cells to invade into the surrounding brain parenchyma is a major clinical issue rendering glioblastoma incurable by conventional therapies. In a previous study, we found that the p75 neurotrophin receptor (p75NTR) significantly enhanced invasion and migration of genetically distinct glioma by a cell autonomous mechanism. In addition, p75NTR was frequently observed in a highly invasive population of cells from freshly resected patient specimens. Importantly, p75NTR was found to mediate glioma invasion by neurotrophin-dependent regulated intramembrane proteolysis (RIP). Blocking of p75NTR proteolysis by the generation of cleavage-resistance mutants, or treatment of animals bearing p75NTR-postive intracranial tumors with γ-secretase inhibitors, significantly inhibited glioma invasion and prolonged survival. Using a large panel of patient-derived-BTICs we have investigated the role of p75NTR in the stem-like compartment. Here we investigate the biological effects of p75NTR down-regulation on glioma derived BTICs. Immunocytochemical studies western blot analysis reveal that p75NTR is variably expressed on BTICs and that treatment with γ-secretase inhibitors significantly decreases BTIC invasion in 3D cultures in vitro. Down-regulation of p75NTR using shRNA significantly decreases BTICs invasion, proliferation and self-renewal ability. Moreover, p75NTR was present on as a component of BTIC-derived extracellular vesicles (EVs) that are implicated in tumor cell invasion through a cell non-autonomous mechanism. We found that p75NTR containing EVs promote invasion of non-invasive glioma cells. The composition of p75NTR containing EVs and their roles in glioma invasion are currently being investigated.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".