TYRP1 defines a proliferative melanoma cell subpopulation, driving malignant progression and therapy resistance via the GPNMB-Notch1-SOX10/MITF axis.

Summary

Using scRNA-seq, organoids, engineered cell lines, and mouse xenografts, the study shows that TYRP1 marks and sustains a proliferative melanoma subpopulation via a GPNMB–Notch1–SOX10/MITF feedback loop. TYRP1-high tumors resist immune checkpoint blockade but are more sensitive to dabrafenib, highlighting biomarker-guided therapeutic stratification.

Key Findings

• TYRP1 identifies a transcriptionally distinct, highly proliferative melanoma subpopulation associated with poorer survival.
• TYRP1 induces GPNMB, activating Notch1 and upregulating SOX10/MITF to form a self-reinforcing proliferative loop.
• Inhibiting GPNMB or Notch1 disrupts the loop and suppresses tumor growth in vitro and in vivo.
• TYRP1-overexpressing tumors resist immune checkpoint blockade but show increased sensitivity to dabrafenib.

Clinical Implications

TYRP1 could serve as a biomarker to preferentially select BRAF pathway inhibition over immune checkpoint blockade in TYRP1-high tumors and motivates trials combining or sequencing Notch1/GPNMB inhibitors. Diagnostic assays for TYRP1 may guide precision oncology.

Limitations

• Preclinical nature without prospective clinical validation of TYRP1-guided therapy
• Potential dataset selection biases and limited assessment of metastatic capacity changes

Future Directions

Prospective clinical studies to validate TYRP1 as a predictive biomarker; early-phase trials testing Notch1/GPNMB inhibition and therapy sequencing in TYRP1-high melanoma.