Lipocalin-2+ Mast Cells in Lymph Nodes Promote Cancer Stemness by a Mitochondrial-derived Peptide

Here, using single-cell RNA sequencing data, photoconversion technique, MC-deficient KitW-sh and lipocalin-2 deficient mice, we show that MCs in LNs promote stemness of tumour cells metastasizing to LNs and their further dissemination to distant organs. Mechanistically, lipocalin-2, secreted by LN MCs, facilitates mitochondrial RNA leakage by mitochondrial permeability transition pore (mPTP) opening, which promotes stem cell transcription factor-TFCP2L1 activity by mitochondrial peptide MOTS-c.

Aptamer of MOTS-c or lipocalin-2 neutralization inhibit MC-mediated stemness of tumour cells and reduce lung metastasis burden in vivo. Collectively, we uncover the new function of LN MCs and provide an appealing therapeutic strategy for the progression of carcinoma.