Talk abstracts
Talk on Tuesday 04:30-04:45pm submitted by Justin Middleton
The stress-inducible gene, Atf3, in myeloid cells regulates chemotherapy-exacerbated breast cancer colonization.
Justin D. Middleton (MCDB), Jared T. Fehlman (College of Arts and Sciences, OSU), Tsonwin Hai (Biological Chemistry and Pharmacology, College of Medicine)
Abstract:
Emerging evidence indicates that chemotherapy can paradoxically produce a pro-cancer response by triggering tissue repair pathways, inflammation and immune suppression. We have previously shown that chemotherapy exacerbates metastasis in a mouse model of breast cancer, even while shrinking the primary tumor. This effect largely disappeared in ATF3 knockout (KO) mice. ATF3 is a stress-inducible gene that encodes a transcription factor that regulates hundreds of genes, and is upregulated by chemotherapy. We hypothesized that chemotherapy-derived stress changes the host in an ATF3-dependent manner that produces a better “soil” in which metastasizing cancer cells can grow. In order to directly test the effects of chemotherapy on the site of metastasis, we developed an experimental metastasis model where wildtype (WT) or ATF3 KO mice are treated with cyclophosphamide – a widely used chemotherapeutic drug – four days before breast cancer cells are intravenously injected. By the point that cancer cells are injected, the drugs have been eliminated from the body, ensuring that the chemotherapy has no effect on the cancer cells, only the host. We found that chemotherapy led to an increase in cancer cell colonization of the lungs only in WT mice, indicating that treatment changes the metastatic environment in an ATF3-dependent manner. We detected an increase in immunosuppressive inflammatory monocytes in the lung following chemotherapy in WT, but not KO mice, along with elevated levels of myeloid progenitors in the bone marrow of WT-treated mice. Based on these results, we tested the importance of ATF3 in myeloid cells. We found that depleting ATF3 only in myeloid cells using conditional KO mice resulted in a significant decrease in cancer burden in the lungs, and that injecting myeloid cells collected from WT-treated mice into KO mice increased cancer cell seeding, suggesting that myeloid cells are both necessary and sufficient for chemo-exacerbated colonization. Myeloid cells are known to prevent cancer cell death and increase extravasation—key steps for cancer cells during the colonization process. Future work will uncover if these mechanisms are behind this phenotype, with the overall goal of identifying cellular and molecular targets that may improve the efficacy of chemotherapy.
Keywords: metastasis, chemotherapy, immunology