Hepatocytes direct the formation of a pro-metastatic niche in the liver.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA431170 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6502450.fastq.gz | Fastqsanger.gz | |||
| SRR6502451.fastq.gz | Fastqsanger.gz | |||
| SRR6502452.fastq.gz | Fastqsanger.gz | |||
| SRR6502453.fastq.gz | Fastqsanger.gz | |||
| SRR6502454.fastq.gz | Fastqsanger.gz |
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Project description:The liver is the most common site of metastatic disease in gastrointestinal malignancies, including pancreatic ductal adenocarcinoma (PDAC). While this metastatic tropism may reflect mechanical trapping of tumor cells that enter the circulation, liver metastasis is also dependent, at least in part, on the formation of a “pro-metastatic” niche that supports tumor cell seeding and colonization in the liver. However, mechanisms that orchestrate the establishment of this niche are poorly understood. Here, we show that hepatocytes coordinate accumulation of myeloid cells and fibrosis within the liver, the two defining features of a pro-metastatic niche. Early during pancreatic tumorigenesis in mice, hepatocytes demonstrate activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling and increased production of serum amyloid A1 and A2 (SAA). Overexpression of SAA by hepatocytes also occurs in PDAC patients with liver metastases, and many patients with locally advanced and metastatic disease display elevated levels of circulating SAA. STAT3 activation in hepatocytes and the subsequent production of SAA are dependent on interleukin 6 (IL-6) that is released into the circulation by non-malignant cells that reside adjacent to malignant cells in the pancreas. Genetic ablation or blockade of components of IL-6/STAT3/SAA signaling in hepatocytes effectively prevents the establishment of a pro-metastatic niche and inhibits metastatic seeding in the liver. Collectively, our data reveal an intercellular network underpinned by hepatocytes that forms the basis for a pro-metastatic niche in the liver and identify new therapeutic targets for pancreatic cancer.
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Project description:The liver is the most common site of metastatic disease1. Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a 'pro-metastatic' niche that supports the spread of tumour cells to the liver2,3. The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6-STAT3-SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets.
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