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Ectopic Osx+ Cells Affect Tumor Growth

ABSTRACT: Tumor growth and metastases are dependent on interactions between cancer cells and the local environment. Expression of the cell-cell adhesion molecule N-cadherin (Ncad) is associated with highly aggressive cancers, and its expression by osteogenic cells has been proposed to provide a molecular “dock” for disseminated tumor cells to establish pre-metastatic niches within the bone. Contrary to expectations, the breast cancer cells were able to form tumors in bone and to induce osteolysis in Cdh2-cKO as well as in control mice. Notably, subcutaneous tumors grew larger in Cdh2-cKO relative to control littermates. Cell tracking experiments using the Ai9 reporter revealed the presence of Osx+ and Ncad+ cells in the stroma of extra-skeletal tumors and in a small population of lung cells, a frequent site of breast cancer metastasis. Gene expression analysis by RNAseq of CD45- Osx+ cells isolated from extra-skeletal tumors revealed alterations of pro-tumorigenic signaling pathways in Cdh2-cKO cells relative to control Osx+ cells. Also surprisingly, we find Osx+ cells present in the circulation, and the majority of tumor-associated and circulating Osx+ cells express the hematopoietic marker CD45, have a phenotypic profile resembling that of tumor infiltrating myeloid and lymphoid populations, but with higher expression of lymphocytic immune suppressive genes. Our results indicate that Osx marks distinct tumor promoting CD45- and CD45+ populations and challenge the dogma that osteogenic and hematopoietic markers are mutually exclusive. They also show that Ncad in CD45- Osx+ cells is not necessary for the establishment of bone metastases, but in extra-skeletal tumors it regulates pro-tumorigenic support by the microenvironment.

ORGANISM(S): Mus musculus

PROVIDER: GSE143586 | GEO | 2020/08/13

REPOSITORIES: GEO

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Project description:Oncogenic signaling of the niche can have a severe effect on the hematopoietic compartment and could contribute or play an active role during the development of human leukemia predisposition syndromes. To provide insights into the mechanisms that underlie this concept, as well as their relevance to disease, this study uses the leukemia predisposition syndrome Shwachman-Diamond syndrome (SDS) as a model. This leukemia predisposition syndrome is established by constitutive homozygous or compound heterozygous loss-of-function mutations in the gene SBDS. SDS is characterized by skeletal defects and a striking predisposition for the development of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Loss of Sbds in the hematopoietic compartment does not results in the induction of MDS or AML, however, could have an indirect effect on the hematopoietic system through the disruption of niche cells.<br>This submission concerns itself with gene expression profiling of transgenic mice. Osterix1 (Osx) is a zinc-finger transcriptional factor essential for osteoblast differentiation in mice and is expressed in cells of the mesenchymal lineage. A bacterial artificial chromosome (BAC) was modified such that it expressed the green fluorescent protein (GFP)::Cre recombinase (GFP::Cre) fusion protein. The artificial construct was inserted into the Osterix gene (Osx1, Sp7), enabling fusion gene GFP::Cre to be expressed from the Osx promotor (Osx1-GFP::Cre) and thereby creating transgenic mice. Cells isolated from these mice are therefore termed Osx::GFP cells. The Osx-GFP-Cre mice were crossed with Sbds f/f (flox/flox, loxp sites are inserted into the gene Sbds enabling the deletion of the region located between these loxp sites) mice to generate the transgenic Osx-GFP-Cre Sbds f/f (OCS) mice. Hence cells expressing the Osx/Sp7 gene therefore express the GFP::Cre fusion protein which enables the prospective isolation of GFP+ cells and it enables the deletion of the Sbds gene through the Cre-mediated recombination of the loxp sites.</br><br> OCS mice have skeletal defects similar to those observed in the human leukemia predisposition syndrome SDS. To obtain a detailed understanding of the underlying mechanisms Osx::GFP+ cells were prospectively isolated from bone cells suspensions, through fluorescence activated cell sorting (FACS), derived from OCS mice. Mutant OCS mice have a homozygous deletion of the Sbds gene in mesenchymal cells (e.g., osteoblasts), while wildtype mice have normal Sbds alleles. The gene expression profiles (GEPs) of both groups of mice were directly compared to determine major transcriptional changes.</br>

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Ectopic Osx+ Cells Affect Tumor Growth

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