JOURNAL ARTICLE

Targeting FAPα-expressing tumor-associated mesenchymal stromal cells inhibits triple-negative breast cancer pulmonary metastasis

Xiaobo Li, Minfeng Chen, Weijin Lu, Jun Tang, Lijuan Deng, Qing Wen, Maohua Huang, Rong Deng, Geni Ye, Wencai Ye, Dongmei Zhang
Cancer Letters 2021 January 19
33482262
Tumor metastasis is the main cause of death in patients with triple-negative breast cancer (TNBC). Bone marrow-derived mesenchymal stem cells (BM-MSCs) have tropism towards tumor tissues, and can be converted into tumor-associated mesenchymal stromal cells (TA-MSCs) to facilitate TNBC metastasis through interactions with tumor-associated macrophages (TAMs). However, the underlying molecular mechanisms are complex and unclear, and effective strategies to suppress tumor metastasis via eliminating TA-MSCs are still lacking. Here, we demonstrate that fibroblast activation protein alpha (FAPα) was overexpressed in TA-MSCs, which prompts TA-MSCs to secrete multiple C-C motif chemokine ligands, promoting C-C motif chemokine receptor 2 (CCR2)+ TAM recruitment and facilitating TAM polarization into the M2 phenotype, thereby promoting TNBC pulmonary metastasis. Z-GP-DAVLBH, an FAPα-activated vinblastine prodrug, induces FAPα+ TA-MSC apoptosis, which significantly suppresses CCR2+ TAM recruitment and polarization, thus inhibiting pulmonary metastasis of orthotopic TNBC cell-derived xenografts and patient-derived xenografts. This study provides insight into an important role of FAPα in mediating TA-MSC-induced TNBC metastasis and provides compelling evidence that targeting TA-MSCs with an FAPα-activated prodrug is a promising strategy for suppressing TNBC metastasis.

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