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In vivo interaction screening reveals liver-derived constraints to metastasis [Single Cell Multiome ATAC + Gene Expression]

ABSTRACT: It is estimated that only 0.02% of disseminated tumor cells are able to seed overt metastases1. While this suggests the presence of environmental constraints to metastatic seeding, the landscape of host factors controlling this process remains largely unknown. Combining transposon technology2 and fluorescent niche labeling3, we developed an in vivo CRISPR activation screen to systematically investigate the interactions between hepatocytes and metastatic cells. Our approach enabled the identification of Plexin B2 as a critical host-derived regulator of liver colonization in colorectal, pancreatic cancer and melanoma syngeneic mouse models. We dissect a mechanism by which Plexin B2 interacts with class IV semaphorins on tumor cells, leading to Klf4 upregulation and thereby promoting the acquisition of epithelial traits. Our findings highlight the essential role of signals from the liver parenchyma for the seeding of disseminated tumor cells, prior to the establishment of a growth promoting niche. They further suggest that epithelialization is required for the adaptation of CRC metastases to their new tissue environment. Blocking the Plexin B2-semaphorin axis abolishes metastatic colonization of the liver and thus represents a new therapeutic strategy for the prevention of hepatic metastases. Finally, our screening approach, which evaluates host-derived extrinsic signals rather than tumor-intrinsic factors for their ability to promote metastatic seeding, is broadly applicable and lays a framework for the screening of environmental constraints to metastasis in other organs and cancer types.

ORGANISM(S): Mus musculus

PROVIDER: GSE267982 | GEO | 2024/05/21

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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In vivo interaction screening reveals liver-derived constraints to metastasis [Single Cell Multiome ATAC + Gene Expression]

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OmicsDI is part of the ELIXIR infrastructure

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​​​​In vivo interaction screening reveals liver-derived constraints to metastasis [Single Cell Multiome ATAC + Gene Expression]

Dataset's files

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OmicsDI is part of the ELIXIR infrastructure

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In vivo interaction screening reveals liver-derived constraints to metastasis [Single Cell Multiome ATAC + Gene Expression]