Identification and characterization of FGFR2+ hematopoietic stem cell-derived fibrocytes as precursors of cancer-associated fibroblasts induced by esophageal squamous cell carcinoma

Abstract

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. To optimize CAF-targeted therapeutic strategies, we tried to explore the molecular mechanisms of CAF generation in this study. 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. The mechanisms were further verified by using different models both in vitro and in vivo. Results We found that FGFR2+ hematopoietic stem cell (HSC)-derived fibrocytes could be induced by ESCC cells, recruited into tumor xenografts, and differentiated into functional CAFs. They were mobilized by cancer-secreted FGF2 and recruited into tumor sites via the CXCL12/CXCR4 axis. Moreover, they differentiated into CAFs through the activation of YAP-TEAD complex, which is triggered by directly contracting 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 hold promise for locally activation of genetically encoded therapeutic payloads at tumor sites. Conclusions 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 tumor cells.

Targeting MFGE8 secreted by cancer-associated fibroblasts blocks angiogenesis and metastasis in esophageal squamous cell carcinoma

“…The secretion of specific regulatory factors by CAFs plays a crucial role in driving cancer progression. In our prior investigation, we presented evidence showing that fibrocytes derived from FGFR2+ hematopoietic stem cells can be induced by ESCC cells, recruited into tumor xenografts, and then differentiated into functional cancer-associated fibroblasts (CAFs) ( 15 ). To gain a better understanding of the role of CAFs in ESCC, RNA-seq was performed to compare gene expression profiles between CAFs and their progenitor cells, circulating fibrocytes.…”

Inhibition of FGFR2 Signaling by Cynaroside Attenuates Liver Fibrosis

“…In past studies, FGFR2 has shown the potential to be used as a target for the treatment of liver fibrosis [17,19,[21][22][23][24]. Current evidence suggests that FGFR2 may be a promising target [25][26][27], but more research is needed to determine the efficacy of FGFR2 as a target for liver fibrosis treatment as well as to fully understand the mechanisms behind its involvement in TGF-β signaling.…”