Murine breast cancers disorganize the liver transcriptome in a zonated manner

Abstract

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.

Low albumin status accompanies multi-layered immunosuppressive phenotypes in metastatic breast cancer patients

“…Comprehensive measurements of diverse genes and molecules (i.e., omics analysis) against host organs and cells in cancer-bearing conditions is a promising method to understand cancer's adverse effects on the host. To date, a relatively non-biased approach led to the identification of altered metabolism in various metabolic organs, dysregulation in the immune system, and so on., as exemplified by but not limited to a series of previous reports 13,14,15,16,17,18,19 . Measuring molecules from different sources (e.g., blood and immune cells) is of particular significance because it would enable the thorough characterization of disrupted homeostasis.…”

“…We do not exclude the possibility of the involvement of other non-immune cell types, such as hepatocytes and muscle cells, in the immunosuppressive phenotypes. Hepatocytes are the major site of albumin production 14 . Thus, low albumin status most likely indicates liver abnormalities.…”

Progressive, multi‐organ, and multi‐layered nature of cancer cachexia

“…28 We observed that, in control mice, expression of genes associated with the "xenobiotic catabolic process" was highly active in hepatocytes harboring high expression of Cyp2e1, a marker for liver zonation. 28 However, this localized expression was not observed in the livers of 4T1-bearing mice, suggesting that the presence of 4T1 breast cancer disrupted zonated expression of genes involved in the "xenobiotic catabolic process. 28 " In addition, we discovered cancer-induced switching of the biological functions of Albumin (Alb)-high hepatocytes in the liver from metabolism to acute phase response.…”

“…28 However, this localized expression was not observed in the livers of 4T1-bearing mice, suggesting that the presence of 4T1 breast cancer disrupted zonated expression of genes involved in the "xenobiotic catabolic process. 28 " In addition, we discovered cancer-induced switching of the biological functions of Albumin (Alb)-high hepatocytes in the liver from metabolism to acute phase response. 28 In 4T1-bearing mice, genes associated with the "acute phase response" were upregulated in a zonated manner, having higher expression levels in Alb-high zones.…”

“…We recently found that distant breast cancers can alter the spatial patterns of gene expression in the liver. 28 Spatially-regulated gene expression in the liver is critical for liver functioning and is called liver zonation. We used spatial transcriptomics and single-cell RNA-seq to investigate the spatial variation of gene expression in the livers of 4T1bearing mice.…”