# Integrating Multi-Omics Atlas to Uncover Genetic and Epigenetic Mechanisms and Reveal Cell State Evolution Across Ecotypes in Male Urological Cancers

## TL;DR

This paper integrates multi-omics data to study genetic and epigenetic mechanisms in male urological cancers, revealing tumor cell evolution and potential therapies.

## Contribution

The study introduces a comprehensive framework integrating scRNA-seq, scATAC-seq, and spatial transcriptomics to uncover tumor cell differentiation and therapeutic targets.

## Key findings

- Tumor cell subclones and chromosomal abnormalities were identified and linked to functional characteristics.
- Transcription factor regulatory networks were mapped through tumor cell differentiation trajectories.
- DNA methylation and SNP integration revealed multilayer regulatory mechanisms of tumor-related genes.

## Abstract

Male urological cancers, including clear cell renal cell carcinoma (ccRCC), bladder cancer (BC), and prostate cancer (PCa), are characterized by extensive heterogeneity and complex ecosystems, yet the underlying mechanisms remain incompletely understood. In this study, scRNA-seq, scATAC-seq and spatial transcriptomics data are integrated to systematically characterize the features of the tumor microenvironment (TME). We identify tumor cell subclones and elucidate the impact of chromosomal abnormalities on their characteristic functions. We further identify transcription factor regulatory networks by analyzing tumor cell differentiation trajectories. Importantly, we integrate DNA methylation and SNP information to deeply dissect the tumor cell differentiation process, revealing the multilayer regulatory mechanisms of tumor-related genes. Additionally, we reveal the evolution of cellular states across ecotypes to provide a more comprehensive characterization of TME. Finally, we screened potential therapeutic agents targeting the molecular mechanisms underlying tumor cell differentiation (Amivantamab in ccRCC, Levothyroxine in BC, Ouabain in PCa) and signature genes of ecotype. In conclusion, our work establishes a comprehensive framework for tumor assessment and informs the development of precision therapeutic strategies.