| Popis: |
Metastasis is the primary cause of mortality in breast cancer patients but the exact mechanisms governing malignant progression remain unclear. Recent studies have highlighted the role of the tumor microenvironment in promoting metastatic tumor growth. In particular, tumor associated macrophages (TAMs) are known to actively collaborate with tumor cells in mediating several steps of the metastatic cascade. Deciphering how tumor cells rewire regulatory networks in tumor associated macrophages (TAMs) will be critical for the development of effective therapies to combat metastatic disease. CSF1 or M-CSF is a key cytokine implicated in driving the proliferation, survival and differentiation of macrophages. It is well established that CSF1 plays a major role in the recruitment of TAMs to the primary tumor site. However, specific regulatory networks activated by CSF1 in the metastatic milieu are yet to be delineated. In the present study, we determined that CSF1 signaling is activated in metastatic TAMs in mouse models of metastatic breast cancer. ETS2, a critical downstream effector of the CSF1 signaling pathway, induces the expression of miR-21 and miR-29a in TAMs during metastatic tumor progression. Consistent with our mouse data, analysis of human metastatic breast cancer samples revealed that CSF1 signaling is activated even in human TAMs and Csf1r+ cells in brain metastases express miR-21 and mir-29a.Employing both loss-of-function and gain-of-function approaches, we established the direct role of these microRNA in promoting tumor cell proliferation and angiogenesis. We propose that miR-21 and miR-29a mediate their function through their repression of two classes of genes: promoters of anti-tumor immunity (`M1’ genes) and negative regulators of angiogenesis. Further, we demonstrate that there is an expansion of a CSF1 responsive myeloid population in the bone marrow of metastatic tumor bearing mice and the blood of patients suffering from metastatic disease. Intriguingly, we observed a positive correlation between metastatic tumor burden and miR-21 and mir-29a expression in these cells. Studies utilizing mouse models of metastatic melanoma revealed that miR-21 and miR-29a expression is also elevated in metastatic melanoma associated macrophages, indicating that CSF1 driven alterations in macrophages might be vital for solid tumor metastasis in general.In addition to the induction of oncogenic miRs, we uncover a novel function of the CSF1-ETS2 signaling axis in promoting metastatic tumor growth via the activation of expression of the chemoattractants S100a8 and S100a9. These molecules facilitate the recruitment of pro-tumor CD11b+ GR1+ myeloid suppressor cells to metastatic sites, thus accelerating metastatic tumor progression. In summary, we have delineated novel transcriptional and post-transcriptional regulatory mechanisms activated by the CSF1-ETS2 signaling axis in metastatic tumor associated macrophages that fuel secondary tumor growth through the establishment of a positive feedback loop with tumor cells. |
