Cancers are a group of heterogeneous diseases characterized by the acquisition of functional capabilities during the transition from a normal to a neoplastic state. Powerful experimental and computational tools can be applied to elucidate the mechanisms of occurrence, progression, metastasis, and drug resistance; however, challenges remain. Bulk RNA sequencing techniques only reflect the average gene expression in a sample, making it difficult to understand tumor heterogeneity and the tumor microenvironment. The emergence and development of single-cell RNA sequencing (scRNA-seq) technologies have provided opportunities to understand subtle changes in tumor biology by identifying distinct cell subpopulations, dissecting the tumor microenvironment, and characterizing cellular genomic mutations. Recently, scRNA-seq technology has been increasingly used in cancer studies to explore tumor heterogeneity and the tumor microenvironment, which has increased the understanding of tumorigenesis and evolution. This review summarizes the basic processes and development of scRNA-seq technologies and their increasing applications in cancer research and clinical practice. 

Advances in single-cell RNA sequencing and its applications in cancer research

Accumulated evidence highlights the significance of the crosstalk between epigenetic and epitranscriptomic mechanisms, notably 5-methylcytosine (5mC) and N6-methyladenosine (m6A). Herein, we conducted a widespread analysis regarding the crosstalk between 5mC and m6A regulators in hepatocellular carcinoma (HCC).Pan-cancer genomic analysis of the crosstalk between 5mC and m6A regulators was presented at transcriptomic, genomic, epigenetic, and other multi-omics levels. Hub 5mC and m6A regulators were summarized to define an epigenetic and epitranscriptomic module eigengene (EME), which reflected both the pre- and post-transcriptional modifications.5mC and m6A regulators interacted with one another at the multi-omic levels across pan-cancer, including HCC. The EME scoring system enabled to greatly optimize risk stratification and accurately predict HCC patients' clinical outcomes and progression. Additionally, the EME accurately predicted the responses to mainstream therapies (TACE and sorafenib) and immunotherapy as well as hyper-progression. In vitro, 5mC and m6A regulators cooperatively weakened apoptosis and facilitated proliferation, DNA damage repair, G2/M arrest, migration, invasion and epithelial-to-mesenchymal transition (EMT) in HCC cells. The EME scoring system was remarkably linked to potential extrinsic and intrinsic immune escape mechanisms, and the high EME might contribute to a reduced copy number gain/loss frequency. Finally, we determined potential therapeutic compounds and druggable targets (TUBB1 and P2RY4) for HCC patients with high EME.Our findings suggest that HCC may result from a unique synergistic combination of 5mC-epigenetic mechanism mixed with m6A-epitranscriptomic mechanism, and their crosstalk defines therapeutic response and pharmacogenomic landscape. 

/pdf/crosstalk-between-5-methylcytosine-and-n6-methyladenosine-2sw3ezxa.pdf

Crosstalk between 5-methylcytosine and N6-methyladenosine machinery defines disease progression, therapeutic response and pharmacogenomic landscape in hepatocellular carcinoma

Macrophages are heterogeneous and play critical roles in development and disease, but their diversity, function, and specification remain inadequately understood during human development. We generated a single-cell RNA sequencing map of the dynamics of human macrophage specification from PCW 4–26 across 19 tissues. We identified a microglia-like population and a proangiogenic population in 15 macrophage subtypes. Microglia-like cells, molecularly and morphologically similar to microglia in the CNS, are present in the fetal epidermis, testicle, and heart. They are the major immune population in the early epidermis, exhibit a polarized distribution along the dorsal-lateral-ventral axis, and interact with neural crest cells, modulating their differentiation along the melanocyte lineage. Through spatial and differentiation trajectory analysis, we also showed that proangiogenic macrophages are perivascular across fetal organs and likely yolk-sac-derived as microglia. Our study provides a comprehensive map of the heterogeneity and developmental dynamics of human macrophages and unravels their diverse functions during development. 

An immune cell atlas reveals the dynamics of human macrophage specification during prenatal development

https://doi.org/10.1016/j.jcmgh.2023.01.006

Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and Cholangiocarcinoma

Fetal liver development and implications for liver disease pathogenesis.

Liver cancer arises from the evolutionary selection of the dynamic tumor microenvironment (TME), in which the tumor cell generally becomes more heterogeneous; however, the mechanisms of TME-mediated transcriptional diversity of liver cancer remain unclear. Here, we assess transcriptional diversity in 15 liver cancer patients by single-cell transcriptome analysis and observe transcriptional diversity of tumor cells is associated with stemness in liver cancer patients. Tumor-associated fibroblast (TAF), as a potential driving force behind the heterogeneity in tumor cells within and between tumors, was predicted to interact with high heterogeneous tumor cells via COL1A1-ITGA2. Moreover, COL1A1-mediated YAP-signaling activation might be the mechanistic link between TAF and tumor cells with increased transcriptional diversity. Strikingly, the levels of COL1A1, ITGA2, and YAP are associated with morphological heterogeneity and poor overall survival of liver cancer patients. Beyond providing a potential mechanistic link between the TME and heterogeneous tumor cells, this study establishes that collagen-stimulated YAP activation is associates with transcriptional diversity in tumor cells by upregulating stemness, providing a theoretical basis for individualized treatment targets. 

/pdf/single-cell-transcriptional-diversity-and-intercellular-hgna8rb5.pdf

Single cell transcriptional diversity and intercellular crosstalk of human liver cancer

Rapid solidification of simulated radioactive contaminated soil by continuous microwave sintering: Effects of temperature and doping level.

Vascular abnormalities and hypoxia in solid tumors limit the efficacy of chimeric antigen receptor (CAR) T-cell therapy. This study proposes a biomimic nanoenzyme, Lenv@BSA-PtNPs, combining platinum nanoparticles (PtNPs) and lenvatinib, to address these challenges in a hepatocellular carcinoma (HCC) nonobese diabetic (NOD) mice model. Lenv@BSA-PtNPs were designed using albumin as a solubilizer, embedding lenvatinib via hydrophobic interactions and facilitating in situ PtNPs generation. The nanoenzyme functions as a catalase, converting H2O2 to O2, downregulating hypoxia-inducible factor (HIF-1), and normalizing tumor vasculature. Its efficacy was evaluated in a glypican-3 (GPC3)-CAR T-cell therapy model for HCC. Lenv@BSA-PtNPs significantly improved tumor oxygenation, normalized vasculature, and enhanced GPC3-CAR T-cell infiltration into tumors. This led to potent antitumor effects and prolonged survival in the HCC mouse model. Lenv@BSA-PtNPs provide a simple and effective strategy to enhance CAR-T cell accumulation and efficacy by ameliorating hypoxia and normalizing tumor vasculature, offering a promising approach for improving CAR-T therapy in solid tumors.

Bidirectional roles of nanoenzymes in enhancing GPC3-CAR T cell infiltration and cancer immunotherapy

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Single cell transcriptional diversity and intercellular crosstalk of human liver cancer

Rapid solidification of simulated radioactive contaminated soil by continuous microwave sintering: Effects of temperature and doping level.

Bidirectional roles of nanoenzymes in enhancing GPC3-CAR T cell infiltration and cancer immunotherapy