Abstract 54P
Background
Lymph nodes (LN) are the most frequent metastasis sites in oesophageal squamous cell carcinoma (ESCC), but the associated mechanisms are poorly understood. Tumor cells seed and survive at LN during the early adaptation step, which is the bottleneck for successful metastasis. However, the phenotypic and molecular characteristics of heterogeneous metastatic cells that contribute to such a challenging process remain elusive.
Methods
We established a human xenograft spontaneous LN metastasis model to capture tumor cell dissemination behaviors. We conducted single-cell RNA sequencing on tumor cells collected from primary tumors and metastatic LN to profile the dynamic cellular and molecular changes in tumor cells associated with LN metastasis. We further identified and characterized the early metastasis tumor cells in LN through in vitro and in vivo functional assays.
Results
We revealed that LN metastasis is initiated by rare ESCC subpopulations with stemness and mesenchymal regulatory gene expression signatures. These tumor cell subpopulations are critical to driving metastasis in distant organs through the blood circulation in mice, supporting the metastasis-initiating cells (MICs) properties. Importantly, these key driver cells were observed to convert the metabolic strategy to mitochondrial oxidative phosphorylation (OXPHOS) during cell seeding in the LN. Enhanced OXPHOS in LN metastatic cells is induced by fatty acids and regulated by NRF2 signaling. Pharmacological inhibition of OXPHOS with IACS-010759 markedly attenuated metastasis in mice.
Conclusions
Our results demonstrate the important role of mitochondrial OXPHOS in promoting ESCC metastasis and suggest the clinical therapeutic potential of OXPHOS inhibitors for preventing metastatic spread in ESCC patients.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National Natural Science Foundation of China (82103643, 82072738, 82072731).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
14P - Peripheral immune kinetics in survival prediction of small cell lung cancer patients treated with immune checkpoint blockade therapy
Presenter: MIGUEL GALINDO CAMPOS
Session: Poster session 09
15P - CBL E3 ubiquitin ligases are key inhibitory regulators in PD-1/LAG-3 co-signaling in human cancers, targeted through bispecific co-blockade
Presenter: Luisa Chocarro
Session: Poster session 09
16P - Terminally exhausted CD8+ T cells and increased immunosuppressive soluble factors in malignant ascites of patients with gastric cancer with peritoneal metastasis
Presenter: Hye Sook Han
Session: Poster session 09
17P - Continued expansion of long-lived effect CD8+ T cells associates with durable response post-PD-1 blockade
Presenter: Robert Watson
Session: Poster session 09
18P - Exposure of calreticulin is required for vitamin C immunomediated cancer surveillance
Presenter: Alessandro Cavaliere
Session: Poster session 09
19P - Preclinical and clinical significance of VEGF deprivation in ovarian cancer through a specific active immunotherapy
Presenter: Yanelys Morera
Session: Poster session 09
20P - The essential role of DNA repair in the pharmacological activities of AST-3424
Presenter: Fanying Meng
Session: Poster session 09
21P - Implications of KMT2C knockdown for DNA damage repair in breast cancer
Presenter: Philip Bredin
Session: Poster session 09
22P - Clinical significance of DNA damage response mutations in early stage NSCLC
Presenter: Haoran Zhang
Session: Poster session 09
23P - PMC-309: A highly selective anti-VISTA antibody reverses immunosuppressive TME to immune-supportive
Presenter: Cheon Ho Park
Session: Poster session 09