ETS1 Orchestrates a Hybrid EMT Program Driving Metastasis and Immune Evasion

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• Intratumoral heterogeneity (ITH) drives aggressive cancers, contributing to metastasis and immune evasion.
• Understanding ITH programs is crucial for developing effective cancer treatments.

Purpose of the Study:

• To investigate the transcriptional ITH programs in upper aerodigestive squamous cell carcinoma (UASCC).
• To identify key regulators driving metastasis and immune evasion in UASCC.
• To explore potential therapeutic strategies targeting ITH-driven aggressive cancers.

Main Methods:

• Single-cell RNA sequencing analysis of UASCC cells and patient tumors.
• Identification of transcription factors regulating ITH programs.
• In vivo studies to assess metastatic potential.
• Analysis of immune microenvironment characteristics.
• Clinical correlation analysis with patient survival and treatment response.
• Drug screening for therapeutic vulnerabilities.

Main Results:

• A hybrid epithelial-mesenchymal transition (hEMT) ITH program was identified, linked to metastatic dissemination in UASCC.
• The transcription factor ETS1 was identified as a master regulator of the hEMT program, promoting metastasis.
• ETS1 also induced an immune-cold tumor microenvironment by activating STAT1 and CD274 (PD-L1), suppressing T cell infiltration.
• High ETS1 expression correlated with poor survival and resistance to immune checkpoint blockade (ICB) in multiple patient cohorts.
• ETS1-high cancers showed vulnerability to HSP90 inhibitors, which suppress ETS1 activity.

Conclusions:

• ETS1 is a critical driver of both tumor metastasis and immune evasion in UASCC.
• HSP90 inhibition represents a promising, tailored treatment strategy for ETS1-driven UASCC.
• Targeting ETS1-driven ITH offers a roadmap for overcoming immunotherapy resistance and treating aggressive cancers.