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Abstract
Background Ferroptosis plays a crucial role in tumor microenvironment (TME). Here, we aim to reveal how FTL-mediated ferroptosis promotes ESCC metastasis by reprogramming the esophageal squamous cell carcinoma (ESCC) microenvironment, thereby providing new therapeutic strategies for ESCC treatment.
Methods Single-cell RNA sequencing (scRNA-seq) data from patients with ESCC lymph node metastasis (LNM) in our laboratory and TCGA (n=81) were included in this study. The expression of FTL in ESCC tissues and corresponding para-cancerous tissues was assessed by immunohistochemistry (IHC). The effects of FTL were investigated in the subcutaneous and LNM mice model.
Results Single-cell RNA sequencing (scRNA-seq) data from patients with ESCC lymph node metastasis in our laboratory showed that ferroptosis played a vital role in promoting ESCC metastasis by reprogramming TME (IDDF2024-ABS-0075 Figure 1. FTL was selected via single-cell analyses of primary and metastatic ecosystems in ESCC). FTL was found to be a specific gene that promoted ESCC lymph node metastasis by altering the TME via ferroptosis (IDDF2024-ABS-0075 Figure 2. Knockdown of FTL inhibits tumor growth and promotes ferroptosis in ESCC). Bioinformatic analyses showed that FTL was highly expressed in both primary and metastatic sites than normal, and patients with high expression had poor prognosis, and its function was related to macrophages in TME. Functional studies have shown that FTL promoted tumor growth, tolerated oxidative stress, reduced the sensitivity of ESCC cells to ferroptosis, facilitated epithelial-mesenchymal transition (EMT) and changed the polarization of macrophages to promote metastasis. Mechanism studies have shown that FTL promotes ESCC development and metastasis via NRF2 pathway and inhibits ferroptosis via NCOA4/FTH1/HMOX1 axis (IDDF2024-ABS-0075 Figure 3. FTL promotes ESCC metastasis and inhibits ferroptosis via NRF2/FTH1/HMOX1 axis). In vivo treatment, Brusatol, an active component of Brucea javanica from traditional Chinese medicine (TCM), was found to have a significant inhibitory effect on ESCC growth and metastasis.
FTL was selected via single-cell analyses of primary and metastatic ecosystems in ESCC
Knockdown of FTL inhibits tumor growth and promotes ferroptosis in ESCC
FTL promotes ESCC metastasis and inhibits ferroptosis via NRF2/FTH1/HMOX1 axis
Conclusions FTL-mediated ferroptosis promoted ESCC growth and metastasis by reprogramming TME. Targeting FTL might provide a novel strategy for ESCC treatment.