mining-spatial-transcriptomics-datasets-using-deepspacedb

Mining Spatial Transcriptomics Datasets using DeepSpaceDB

Spatial transcriptomics is a rapidly evolving technology that enables the capture of gene expression patterns in tissue samples while preserving ...

Tohoku University

Kyoto University

Cancers disrupt host homeostasis in various manners but the identity of host factors underlying such disruption remains largely unknown. Here we show that nicotinamide-N-methyltransferase (NNMT) is a host factor that mediates metabolic dysfunction in the livers of cancer-bearing mice. Multiple solid cancers distantly increase expression of Nnmt and its product 1-methylnicotinamide (MNAM) in the liver. Multi-omics analyses reveal suppression of the urea cycle accompanied by accumulation of amino acids, and enhancement of uracil biogenesis in the livers of cancer-bearing mice. Importantly, genetic deletion of Nnmt leads to alleviation of these metabolic abnormalities, and buffers cancer-dependent weight loss and reduction of the voluntary wheel-running activity. Our data also demonstrate that MNAM is capable of affecting urea cycle metabolites in the liver. These results suggest that cancers up-regulate the hepatic NNMT pathway to rewire liver metabolism towards uracil biogenesis rather than nitrogen disposal via the urea cycle, thereby disrupting host homeostasis.

Remote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase.

The spatially organized gene expression program within the liver specifies hepatocyte functions according to their relative distances to the bloodstream (i.e., zonation), contributing to liver homeostasis. Despite the knowledge that solid cancers remotely disrupt liver homeostasis, it remains unexplored whether solid cancers affect liver zonation. Here, using spatial transcriptomics, we thoroughly investigate the abundance and zonation of hepatic genes in cancer-bearing mice. We find that breast cancers affect liver zonation in various distinct manners depending on biological pathways. Aspartate metabolism and triglyceride catabolic processes retain relatively intact zonation patterns, but the zonation of xenobiotic catabolic process genes exhibits a strong disruption. The acute phase response is induced in zonated manners. Furthermore, we demonstrate that breast cancers activate innate immune cells in particular neutrophils in distinct zonated manners, rather than in a uniform fashion within the liver. Collectively, breast cancers disorganize hepatic transcriptomes in zonated manners, thereby disrupting zonated functions of the liver.

Murine breast cancers disorganize the liver transcriptome in a zonated manner.

Cancers induce the production of acute phase proteins such as serum amyloid alpha (SAA) in the liver and cause inflammation in various host organs. Despite the well-known coincidence of acute phase response and inflammation, the direct roles of SAA proteins in inflammation in the cancer context remains incompletely characterized, particularly . Here, we investigate the  significance of SAA proteins in liver inflammation in the 4T1 murine breast cancer model. 4T1 cancers elevate the expression of SAA1 and SAA2, the two major murine acute phase proteins in the liver. The elevation of  correlates with the up-regulation of immune cell-related genes including neutrophil markers. To examine this correlation in detail, we generate mice that lack  and investigate immune-cell phenotypes. RNA-seq experiments reveal that deletion of  does not strongly affect 4T1-induced activation of immune cell-related genes in the liver. Flow cytometry experiments demonstrate the dispensable roles of SAA1-2 in cancer-dependent neutrophil infiltration to the liver. Consistently, 4T1-induced gene expression changes in bone marrow do not require . This study clarifies the negligible contribution of SAA1-2 proteins in liver inflammation in the 4T1 breast cancer model.

Serum amyloid alpha 1-2 are not required for liver inflammation in the 4T1 murine breast cancer model.

Nicotinamide-N-methyltransferase (NNMT) is an enzyme that consumes S-adenosyl-methionine (SAM) and nicotinamide (NAM) to produce S-adenosyl-homocysteine (SAH) and 1-methylnicotinamide (MNAM). How much NNMT contributes to the quantity regulation of these four metabolites depends on whether NNMT is a major consumer or producer of these metabolites, which varies among various cellular contexts. Yet, whether NNMT critically regulates these metabolites in the AML12 hepatocyte cell line has been unexplored. To address this, we knockdown Nnmt in AML12 cells and investigate the effects of Nnmt RNAi on metabolism and gene expression. We find that Nnmt RNAi accumulates SAM and SAH, whereas it reduces MNAM with NAM being unaltered. These results indicate that NNMT is a significant consumer of SAM and critical for MNAM production in this cell line. Moreover, transcriptome analyses reveal that altered SAM and MNAM homeostasis is accompanied by various detrimental molecular phenotypes, as exemplified by the down-regulations of lipogenic genes, such as Srebf1. Consistent with this, oil-red O-staining experiments demonstrate the decrease of total neutral lipids upon Nnmt RNAi. Treating Nnmt RNAi AML12 cells with cycloleucine, an inhibitor of SAM biogenesis suppresses SAM accumulation and rescues the decrease of neutral lipids. MNAM also shows activity to elevate neutral lipids. These results suggest that NNMT contributes to lipid metabolism by maintaining proper SAM and MNAM homeostasis. This study provides an additional example where NNMT plays a critical role in regulating SAM and MNAM metabolism.

Nicotinamide-N-methyltransferase regulates lipid metabolism via SAM and 1-methylnicotinamide in the AML12 hepatocyte cell line.

Triple-negative breast cancer (TNBC) is the most heterogeneous breast cancer subtype. Partly due to its heterogeneity, it is currently challenging to stratify TNBC patients and predict treatment outcomes.

Time-series blood cytokine profiles correlate with treatment responses in triple-negative breast cancer patients.

Cancer cachexia is a complex, multifaceted condition that negatively impacts the health, treatment efficacy, and economic status of cancer patients. The management of cancer cachexia is an essential clinical need. Cancer cachexia is currently defined mainly according to the severity of weight loss and sarcopenia (i.e., macrosymptoms). However, such macrosymptoms may be insufficient to give clinicians clues on how to manage this condition as these symptoms appear at the late stage of cancer. We need to understand earlier events during the progression of cancer cachexia so as not to miss a clinical opportunity to control this complex syndrome. Recent research indicates that cancer-induced changes in the host are much wider than previously recognized, including disruption of liver function and the immune system. Furthermore, such changes are observed before the occurrence of visible distant metastases (i.e., in early, localized cancers). In light of these findings, we propose to expand the definition of cancer cachexia to include all cancer-induced changes to host physiology, including changes caused by early, localized cancers. This new definition of cancer cachexia can provide a new perspective on this topic, which can stimulate the research and development of novel cancer cachexia therapies.

Progressive, multi-organ, and multi-layered nature of cancer cachexia.

Transcribed enhancer maps can reveal nuclear interactions underpinning each cell type and connect specific cell types to diseases. Using a 5' single-cell RNA sequencing approach, we defined transcription start sites of enhancer RNAs and other classes of coding and noncoding RNAs in human CD4 T cells, revealing cellular heterogeneity and differentiation trajectories. Integration of these datasets with single-cell chromatin profiles showed that active enhancers with bidirectional RNA transcription are highly cell type-specific and that disease heritability is strongly enriched in these enhancers. The resulting cell type-resolved multimodal atlas of bidirectionally transcribed enhancers, which we linked with promoters using fine-scale chromatin contact maps, enabled us to systematically interpret genetic variants associated with a range of immune-mediated diseases.

An atlas of transcribed enhancers across helper T cell diversity for decoding human diseases.

Breast cancer cells suppress the host immune system to efficiently invade the lymph nodes; however, the underlying mechanism remains incompletely understood. Here, we aimed to comprehensively characterise the effects of breast cancers on immune cells in the lymph nodes.

Intra-patient spatial comparison of non-metastatic and metastatic lymph nodes reveals the reduction of CD169 macrophages by metastatic breast cancers.

Cancer is a systemic disease rather than a localized pathology and is characterized by widespread effects, including whole-body exhaustion and chronic inflammation. A thorough understanding of cancer pathophysiology requires a systemic approach that accounts for the complex interactions between cancer cells and host tissues. To explore these dynamics, we employed a comprehensive metabolomic analysis of plasma samples from patients with either esophageal or head and neck squamous cell carcinoma (SCC). Plasma samples from 149 patients were metabolically profiled and correlated with clinical data. Among the metabolites identified, lysophosphatidylcholine (LPC) emerged as the sole biomarker strongly correlated with prognosis. A significant reduction in plasma LPC levels was linked to poorer overall survival. Plasma LPC levels demonstrated minimal correlation with patient-specific factors, such as tumor size and general condition, but showed significant association with the response to immune checkpoint inhibitor therapy. Proteomic and cytokine analyses revealed that low plasma LPC levels reflected systemic chronic inflammation, characterized by high levels of inflammatory proteins, the cytokines interleukin-6 and tumor necrosis factor-α, and coagulation-related proteins. These findings indicate that plasma LPC levels may be used as reliable biomarkers for predicting prognosis and evaluating the efficacy of immunotherapy in patients with SCC.

Article	Year
Remote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase. Nature communications\| PubMed ID: 35705545	2022
Murine breast cancers disorganize the liver transcriptome in a zonated manner. Communications biology\| PubMed ID: 36694005	2023
Serum amyloid alpha 1-2 are not required for liver inflammation in the 4T1 murine breast cancer model. Frontiers in immunology\| PubMed ID: 36817472	2023
Nicotinamide-N-methyltransferase regulates lipid metabolism via SAM and 1-methylnicotinamide in the AML12 hepatocyte cell line. Journal of biochemistry\| PubMed ID: 37014628	2023
Time-series blood cytokine profiles correlate with treatment responses in triple-negative breast cancer patients. British journal of cancer\| PubMed ID: 38238427	2024
Progressive, multi-organ, and multi-layered nature of cancer cachexia. Cancer science\| PubMed ID: 38254286	2024
An atlas of transcribed enhancers across helper T cell diversity for decoding human diseases. Science (New York, N.Y.)\| PubMed ID: 38963856	2024
Intra-patient spatial comparison of non-metastatic and metastatic lymph nodes reveals the reduction of CD169 macrophages by metastatic breast cancers. EBioMedicine\| PubMed ID: 39173531	2024
Plasma Lysophosphatidylcholine Levels Correlate with Prognosis and Immunotherapy Response in Squamous Cell Carcinoma. International journal of molecular sciences\| PubMed ID: 40806656	2025

Shinpei Kawaoka

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