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Background Various epigenetic regulations systematically govern gene expression in cells involving various biological processes. Dysregulation of the epigenome leads to aberrant transcriptional programs and subsequently results in diseases, such as cancer. Therefore, comprehensive profiling epigenomics is essential for exploring the mechanisms underlying gene expression regulation during development and disease. Methods In this study, we developed single‐cell chromatin proteins and accessibility tagmentation (scCPA‐Tag), a multi‐modal single‐cell epigenetic profile capturing technique based on barcoded Tn5 transposases and a droplet microfluidics platform. scCPA‐Tag enables the simultaneous capture of DNA profiles of histone modification and chromatin accessibility in the same cell. Results By applying scCPA‐Tag to K562 cells and a hepatocellular carcinoma (HCC) sample, we found that the silence of several chromatin‐accessible genes can be attributed to lysine‐27‐trimethylation of the histone H3 tail (H3K27me3) modification. We characterized the epigenetic features of the tumour cells and different immune cell types in the HCC tumour tissue by scCPA‐Tag. Besides, a tumour cell subtype (C2) with more aggressive features was identified and characterized by high chromatin accessibility and a lower abundance of H3K27me3 on tumour‐promoting genes. Conclusions Our multi‐modal scCPA‐Tag provides a comprehensive approach for exploring the epigenetic landscapes of heterogeneous cell types and revealing the mechanisms of gene expression regulation during developmental and pathological processes at the single‐cell level. Highlights scCPA‐Tag offers a highly efficient and high throughput technique to simultaneously profile histone modification and chromatin accessibility within a single cell. scCPA‐Tag enables to uncover multiple epigenetic modification features of cellular compositions within tumor tissues. scCPA‐Tag facilitates the exploration of the epigenetic landscapes of heterogeneous cell types and provides the mechanisms governing gene expression regulation. scCPA‐Tag Reveals Multidimensional Epigenetic Heterogeneity.

Dissecting and understanding the cancer ecosystem, especially that around the tumor margins, which have strong implications for tumor cell infiltration and invasion, are essential for exploring the mechanisms of tumor metastasis and developing effective new treatments. Using a novel tumor border scanning and digitization model enabled by nanoscale resolution-SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq), we identified a 500 µm-wide zone centered around the tumor border in patients with liver cancer, referred to as “the invasive zone”. We detected strong immunosuppression, metabolic reprogramming, and severely damaged hepatocytes in this zone. We also identified a subpopulation of damaged hepatocytes with increased expression of serum amyloid A1 and A2 (referred to collectively as SAAs) located close to the border on the paratumor side. Overexpression of CXCL6 in adjacent malignant cells could induce activation of the JAK-STAT3 pathway in nearby hepatocytes, which subsequently caused SAAs’ overexpression in these hepatocytes. Furthermore, overexpression and secretion of SAAs by hepatocytes in the invasive zone could lead to the recruitment of macrophages and M2 polarization, further promoting local immunosuppression, potentially resulting in tumor progression. Clinical association analysis in additional five independent cohorts of patients with primary and secondary liver cancer ( n  = 423) showed that patients with overexpression of SAAs in the invasive zone had a worse prognosis. Further in vivo experiments using mouse liver tumor models in situ confirmed that the knockdown of genes encoding SAAs in hepatocytes decreased macrophage accumulation around the tumor border and delayed tumor growth. The identification and characterization of a novel invasive zone in human cancer patients not only add an important layer of understanding regarding the mechanisms of tumor invasion and metastasis, but may also pave the way for developing novel therapeutic strategies for advanced liver cancer and other solid tumors.

Solid tumors are complex ecosystems, and heterogeneity is the major challenge for overcoming tumor relapse and metastasis. Uncovering the spatial heterogeneity of cell types and functional states in tumors is essential for developing effective treatment, especially in invasive fronts of tumor, the most active region for tumor cells infiltration and invasion. We firstly used SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq) with a nanoscale resolution to characterize the tumor microenvironment of intrahepatic cholangiocarcinoma (ICC). Enrichment of distinctive immune cells, suppressive immune microenvironment and metabolic reprogramming of tumor cells were identified in the 500μm-wide zone centered bilaterally on the tumor boundary, namely invasive fronts of tumor. Furthermore, we found the damaged states of hepatocytes with overexpression of Serum Amyloid A (SAA) in invasive fronts, recruiting macrophages for facilitating further tumor invasion, and thus resulting in a worse prognosis. We also confirmed these findings in hepatocellular carcinoma and other liver metastatic cancers. Our work highlights the remarkable potential of high-resolution-spatially resolved transcriptomic approaches to provide meaningful biological insights for comprehensively dissecting the tumor ecosystem and guiding the development of novel therapeutic strategies for solid tumors. Competing Interest Statement The authors have declared no competing interest.

Studying tissue composition and function in non-human primates (NHP) is crucial to understand the nature of our own species. Here, we present a large-scale single-cell and single-nucleus transcriptomic atlas encompassing over one million cells from 43 tissues from the adult NHP Macaca fascicularis. This dataset provides a vast, carefully annotated, resource to study a species phylogenetically close to humans. As proof of principle, we have reconstructed the cell-cell interaction networks driving Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases and intersected our data with human genetic disease orthologous coordinates to identify both expected and unexpected associations. Our Macaca fascicularis cell atlas constitutes an essential reference for future single-cell studies in human and NHP. Competing Interest Statement The authors have declared no competing interest.