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.

中文翻译：

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鼠乳腺癌以分区方式破坏肝脏转录组

肝脏内空间组织的基因表达程序根据肝细胞与血流的相对距离（即分区）指定肝细胞功能，从而有助于肝脏稳态。尽管知道实体癌会远程破坏肝脏稳态，但实体癌是否会影响肝脏分区尚不清楚。在这里，我们使用空间转录组学，彻底研究了荷癌小鼠肝脏基因的丰度和分区。我们发现乳腺癌以各种不同的方式影响肝脏分区，具体取决于生物学途径。天冬氨酸代谢和甘油三酯分解代谢过程保留了相对完整的分区模式，但异生分解代谢过程基因的分区表现出强烈的破坏。急性期反应以分区方式诱导。此外，我们证明乳腺癌以不同的分区方式激活先天免疫细胞，特别是中性粒细胞，而不是在肝脏内以统一的方式激活。总的来说，乳腺癌以分区方式破坏肝脏转录组，从而破坏肝脏的分区功能。