Hematopoietic stem cell-derived fibrocytes as targets and tools for cancer therapy: mechanisms and therapeutic implications

Background: Cancer-associated fibroblast (CAF) is an ideal target for cancer treatment. Recent studies have focused on eliminating CAFs and their effects by targeting their markers or blocking individual CAF-secreted factors. However, these strategies have been limited by their specificity for targeting CAFs and effectiveness in blocking widespread influence of CAFs. Here, we aimed to explore the molecular mechanisms of CAF generation and optimize CAF-targeted therapeutic strategies. Methods: : Using FGFR2 as a tracing marker, we identified a novel origin of CAFs in esophageal squamous cell carcinoma (ESCC). Furthermore, we successfully isolated CAF precursors from peripheral blood of ESCC patients and explored the mechanisms underlying their expansion, recruitment and differentiation via RNA-sequencing and bioinformatics analysis. Results: : We found that FGFR2 + hematopoietic stem cell (HSC)-derived fibrocytes could be induced by ESCC cells, homing into tumor xenografts, and differentiate into functional CAFs. They could be mobilized by cancer-secreted FGF2 and recruited into tumor sites via the CXCL12/CXCR4 axis. Moreover, they differentiate into CAFs through the activation of YAP-TEAD complex which is trigger by directly contract with tumor cells. FGF2 and CXCR4 neutralizing antibodies could effectively block the mobilization and recruitment process of FGFR2 + CAFs. The YAP-TEAD complex-based mechanism can be used to locally activate the production of genetically encoded therapeutic payloads in tumor sites. Conclusion: We identified a novel CAF origin and systematically studied the process of mobilization, recruitment, and maturation of CAFs in ESCC under the guidance of tumor cells. These findings give rise to new approaches that target CAFs before their incorporation into tumor stroma and use CAF- precursors as cellular vehicles to target cancer cells.