Tumor extracellular vesicles carrying phosphatidylserine activate microglia via TREM2, enhancing neuroprotective functions. This is interesting discovery biology but not trial-ready. Requires characterization of PS exposure, EV cargo composition, and demonstration that EVs directly mediate the cystatin-C effect.
Curated pathway from expert analysis
flowchart TD
A["Amyloid-beta Plaques<br/>Phospholipid Ligands"]
B["TREM2 Receptor<br/>Ligand Binding"]
C["TYROBP/DAP12<br/>ITAM Phosphorylation"]
D["SYK Kinase<br/>Activation"]
E["PLCG2<br/>IP3 + DAG Generation"]
F["Ca2+ Release<br/>Cytoskeletal Remodeling"]
G["Microglial Phagocytosis<br/>Plaque Compaction"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for TREM2 ligands on tumor EVs from GTEx v10.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for TREM2 ligands on tumor EVs.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF tumor EVs are pre-incubated with phosphatidylserine-blocking agent (Annexin V, 20 μg/mL) before administration to human iPSC-derived microglia, THEN Annexin V-blocked EVs will show ≥60% reduction i | Cystatin-C concentration in culture supernatant: untreated tumor EVs yield ≥150 pg/mL vs Annexin V-blocked EVs yield ≤60 pg/mL (representing ≥60% reduction) | — no observation — | pending | 0.45 |
| IF primary mouse microglia (from TREM2-WT vs TREM2-KO littermates) are treated with tumor-derived EVs isolated from B16-F10 melanoma cells, THEN TREM2-WT microglia will show ≥50% increase in TREM2 dow | TREM2-dependent microglial activation marker upregulation by phospho-flow cytometry: TREM2-WT shows ≥2-fold increase in p-Syk MFI vs vehicle control, while TREM | — no observation — | pending | 0.55 |