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The “effect” of T staging on resectable metastatic liver colorectal cancer/Early T stage is associated with poor prognosis in patients with metastatic liver colorectal cancer

ABSTRACT: The “effect” of T staging on resectable metastatic liver colorectal cancer/Early T stage is associated with poor prognosis in patients with metastatic liver colorectal cancer

PROVIDER: PRJNA610640 | ENA |

REPOSITORIES: ENA

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The “effect” of T staging on resectable metastatic liver colorectal cancer/Early T stage is associated with poor prognosis in patients with metastatic liver colorectal cancer

Project description:a considerable portion of patients with early T stage who were supposed to have a low distant metastatic probability, were diagnosed with metastatic cancer. Our study aims to evaluate characteristics of T1M1patients via cDNA microarray.

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Single-Cell Transcriptomic Analysis Reveals Dynamic Changes in the Liver Microenvironment During Colorectal Cancer Metastatic Progression

Project description:Background: Metastasis is a leading cause of cancer-related deaths, with the liver being the most frequent site of metastasis in colorectal cancer. Previous studies have predominantly focused on the influence of the primary tumor itself on metastasis, with relatively limited research examining the changes within target organs. Methods: Using an orthotopic mouse model of colorectal cancer, single-cell sequencing was employed to profile the transcriptomic landscape of pre-metastatic and metastatic livers. The analysis focused on identifying cellular and molecular changes within the hepatic microenvironment, with particular emphasis on inflammatory pathways and immune cell populations. Results: A neutrophil subpopulation with high Prok2 expression was identified, showing elevated levels in the pre-metastatic and metastatic liver. Increased infiltration of Prok2⁺ neutrophils correlated with poor prognosis in liver metastatic colorectal cancer patients. In the liver macro-metastatic niche (MMN), these neutrophils showed high App and Cd274 (PD-L1) expression, suppressing macrophage phagocytosis and promoting T-cell exhaustion. Conclusion: A Prok2⁺ neutrophil subpopulation infiltrated both pre-metastatic and macro-metastatic liver environments, potentially driving immunosuppression through macrophage inhibition and T-cell exhaustion. Targeting Prok2⁺ neutrophils could represent a novel therapeutic strategy for preventing liver metastasis in colorectal cancer patients.

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Project description:Colorectal cancer is one of the most frequently occurring malignancies and a major cause of cancer death. Distant metastases in this disease most commonly develop in the liver and are often untreatable. Here, we show that citrullination of the extracellular matrix (ECM) by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases. Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is well recognized in rheumatoid arthritis, but largely undocumented in cancer. PAD4, a key enzyme responsible for catalyzing citrullination, is produced by metastatic colorectal cancer cells and found at higher levels in human liver metastases than in normal liver. Functional significance for citrullination in metastatic growth was evident in murine models where inhibition of citrullination, either globally by pharmacologic inhibition of PADs or specifically in colorectal cancer cells by PAD4 knockdown substantially reduced liver metastatic burden. Additionally, citrullination of a key ECM component collagen type I led to greater adhesion and decreased migration of colorectal cancer cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition (MET) and liver metastasis. Overall, our study revealed the potential for PAD4-dependant citrullination to drive the progression of liver metastasis. These data indicate that inhibition of citrullination could be exploited to prevent the development of liver metastases in colorectal cancer.

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Spatial transcriptomics of human colorectal cancer liver metastatic samples

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