RUNX1T1-HDAC Reprogramming of the HOX Code Signaling Drives a Targetable Pan-Cancer Lineage Plasticity

Area of Science:

• Oncology
• Cancer Biology
• Genomics

Background:

• Lineage plasticity is a key mechanism in cancer therapy resistance and progression.
• Identifying plastic cancer subtypes is challenging due to a lack of pan-cancer markers.
• Homeobox (HOX) genes establish cell identity through specific expression patterns (HOX codes).

Purpose of the Study:

• To identify pan-cancer biomarkers for lineage plasticity.
• To investigate the role of HOX gene expression in cancer lineage identity and plasticity.
• To uncover novel therapeutic vulnerabilities associated with lineage plasticity.

Main Methods:

• Analysis of multi-omics data, including 39 HOX genes from over 80,000 RNA-seq samples across 114 cancer types.
• Differential gene expression analysis to identify plasticity markers.
• Validation using bulk and single-cell RNA-seq from preclinical and clinical cohorts.
• AI-based modeling to identify protein interactions and regulatory complexes.
• Functional studies in prostate cancer models.
• Pharmacologic inhibition of histone deacetylase (HDAC).

Main Results:

• HOX code expression robustly represents cancer cell lineages and identifies novel lineage-plastic subtypes in prostate cancer, lung cancer, and acute myeloid leukemia (AML).
• RUNX1T1 was identified as a novel, consistent pan-cancer marker of plasticity, elevated in plastic subtypes and correlating with HOX codes.
• RUNX1T1 was functionally validated as essential for lineage-plastic programs in prostate cancer.
• AI modeling revealed RUNX1T1 forms a co-repressor complex with NCOR/HDAC, regulating HOX codes and plasticity.
• Pharmacologic HDAC inhibition selectively inhibited the growth of plastic cancer cells.

Conclusions:

• Ectopic RUNX1T1 serves as a pan-cancer biomarker and mediator of lineage plasticity.
• The RUNX1T1-HDAC complex represents a druggable target for treating lineage-plastic cancers.
• Targeting HDACs offers a novel therapeutic strategy against plastic cancer subtypes.