The genomic landscape of clear cell renal cell carcinoma (ccRCC) has a considerable intra-tumor heterogeneity, which is a significant obstacle in the field of precision oncology and plays a pivotal role in metastasis, recurrence, and therapeutic resistance of cancer. The mechanisms of intra-tumor heterogeneity in ccRCC have yet to be fully established. We integrated single-cell RNA sequencing (scRNA-seq) and transposase-accessible chromatin sequencing (scATAC-seq) data from a single-cell multi-omics perspective. Based on consensus non-negative matrix factorization (cNMF) algorithm, functionally heterogeneous cancer cells were classified into metabolism, inflammatory, and EMT meta programs, with spatial transcriptomics sequencing (stRNA-seq) providing spatial information of such disparate meta programs of cancer cells. The bulk RNA sequencing (RNA-seq) data revealed high clinical prognostic values of functionally heterogeneous cancer cells of three meta programs, with transcription factor regulatory network and motif activities revealing the key transcription factors that regulate functionally heterogeneous ccRCC cells. The interactions between varying meta programs and other cell subpopulations in the microenvironment were investigated. Finally, we assessed the sensitivity of cancer cells of disparate meta programs to different anti-cancer agents. Our findings inform on the intra-tumor heterogeneity of ccRCC and its regulatory networks and offers new perspectives to facilitate the designs of rational therapeutic strategies.

The study by Li et al. , “Single-cell transcriptome analysis reveals the association between histone lactylation and cisplatin resistance in bladder cancer”, investigated how histone lactylation contributes to cisplatin resistance in bladder cancer (BCa). Using high-resolution single-cell lineage tracing, the authors identified a distinct subpopulation of BCa cells with enhanced glycolytic metabolism that exhibited significant cisplatin resistance. Further analyses showed significant enrichment of histone H3 lysine 18 lactylation (H3K18la) at the promoter regions of the transcription factors YY1 and YBX1, which promoted their expression and facilitated the development of a drug-resistant phenotype. This study was the first to combine single-cell omics with lactylation modification mechanisms, providing new insights into strategies for overcoming cisplatin resistance in BCa. Nonetheless, potential limitations of the study should be carefully considered.