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Targeting palmitoylation enhances neutrophil-mediated cancer cell killing in liver metastases [scRNA-seq]

ABSTRACT: Liver metastases are frequent and challenging to treat as the liver is a metabolically highly active and immune-tolerant organ. However, how cancer cells exploit the nutrients available in the liver to further exacerbate evasion from the immune system remains largely unknown. We discovered that palmitate availability in the liver promotes neutrophil extracellular traps (NETs) in the presence of cancer cells. Mechanistically, we found that liver metastases from breast and colorectal cancer require the palmitoyltransferase 17 (DHHC17, gene name ZDHHC17) to secrete laminin-511. In turn, neutrophils in the liver metastasis environment responded to laminin-511 by increasing NETosis and decreasing their cancer cell killing capacity. In line, we observed that silencing ZDHHC17 in cancer cells decreased metastasis growth only in the presence of neutrophils, while metastasis growth was rescued in ZDHHC17-silenced metastases upon injection of laminin-511 or inhibition of neutrophil degranulation. Taken together, we found that liver palmitate not only aids cancer cell intrinsic processes but it also enables cancer cells to evade neutrophil destruction.

ORGANISM(S): Mus musculus

PROVIDER: GSE300660 | GEO | 2026/06/29

REPOSITORIES: GEO

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Project description:Breast cancer cells display preferences for specific metastatic sites including the bone, lung and liver. Metastasis is a complex process that relies, in part, on interactions between disseminated cancer cells and resident/infiltrating stromal cells that constitute the metastatic microenvironment. Distinct immune infiltrates can either impair the metastatic process or conversely, assist in the seeding, colonization and growth of disseminated cancer cells. Using in vivo selection approaches, we previously isolated 4T1-derived breast cancer cells that preferentially metastasize to these organs and tissues. In this study, we examined whether the propensity of breast cancer cells to metastasize to the lung, liver or bone is associated with and dependent on distinct patterns of immune cell infiltration. Immunohistocytochemistry and immunohistofluorescence approaches were used to quantify granulocytic infiltrates within distinct metastases and depletion of Gr1+ cells was performed to functionally interrogate the role of myeloid/granulocytic infiltrates in promoting metastasis to these organs. We show that T lymphocytes (CD3+), myeloid-derived/granulocytic cells (Gr-1+) cells and neutrophils (NE+) exhibit the most pronounced recruitment in lung and liver metastases, with markedly less recruitment within bone metastatic lesions. Interestingly, these infiltrating cell populations display different patterns of localization within soft tissue metastases. T lymphocytes and neutrophils are localized around the periphery of liver metastases whereas they were dispersed throughout the lung metastases. Furthermore, Gr-1+ cell-depletion studies demonstrate that infiltrating myeloid-derived/granulocytic cells, including neutrophils, are essential for the formation of breast cancer liver metastases but dispensable for metastasis to the lung and bone. Finally, we demonstrate that neutrophils that infiltrate and surround the liver metastases are polarized towards an N2 phenotype, which have previously been shown to enhance tumor growth and metastasis. Our results demonstrate that the liver metastatic potential of breast cancer cells is heavily reliant on interactions with infiltrating myeloid/granulocytic cells in the liver microenvironment.

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Targeting palmitoylation enhances neutrophil-mediated cancer cell killing in liver metastases [scRNA-seq]

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