Cancers and chemotherapy together are causing widespread inflammatory and oxidative stress and injury that can cause acute and permanent changes and functional impairment of the hematopoietic and immune systems in cancer patients and survivors.
1. Jurecic Lab is using preclinical breast tumor-bearing mouse models treated with neoadjuvant chemotherapy, mouse models of long-term breast cancer survivors, and mouse models of bacterial and viral infections to: (1) characterize in depth long-lasting adverse effects of chemotherapy on the function of the hematopoietic and immune systems and their responses to viral and bacterial infections, (2) investigate the role of inflammation in therapy-induced adverse sequelae, and (3) test whether a) combined treatment with chemotherapy and non-steroidal anti-inflammatory drugs, and b) novel targeted delivery of chemotherapy drugs into the primary tumors and metastatic sites, represent new clinically applicable treatment approaches to minimize or prevent long-lasting adverse effects of therapy by significantly decreasing systemic inflammation.
2. The acute and long lasting impacts of cancer and therapy on the function of hematopoietic and immune systems, and the underlying cellular and molecular mechanisms remain to be fully characterized. The emerging notion is that chemotherapy causes acquired chromosomal and epigenetic changes in healthy cells.
We hypothesize that cancer and chemotherapy are inducing transient and permanent genetic and epigenetic changes in HSPCs and long-lived immune cells, leading to altered gene expression, cell differentiation and function. Through analysis of individual breast cancer-bearing mice treated with maximum tolerated dose (MTD) neoadjuvant chemotherapy and preclinical mouse model of long-term breast cancer survivors the goals of the project is to concurrently: 1) Define acute and long lasting effects of cancer and chemotherapy on the function of HSPCs and immune cells, and 2) Identify cancer/cancer therapy-induced acute and long lasting genetic and epigenetic changes in HSPCs and immune cells. By superimposing detected functional, genetic and epigenetic changes in HSPCs and immune cells this project will determine a) whether cancer and chemotherapy are indeed inducing acute and long-lasting genetic and epigenetic changes in sets of genes known to regulate proliferation, differentiation and function of HSPCs and immune cells, and b) whether these changes correlate with observed altered proliferation, differentiation and function of HSPCs and immune cells in breast cancer-bearing mice and breast cancer survivor mice.
Results of this project will provide essential blueprint for subsequent: a) more comprehensive genetic and epigenetic analysis of acute and long-lasting genetic and epigenetic changes in HSPCs and immune cells of breast cancer-bearing mice and breast cancer survivor mice, and b) identification of causal relationship between altered function of specific immune and hematopoietic cell types and genetic and epigenetic changes that are detectable in these cells. Better understanding of cancer/therapy-induced functional, genetic and epigenetic changes of the immune and hematopoietic systems will open the opportunity to identify cellular and molecular targets for developing interventional approaches that will 1) reduce the incidence of cancer/therapy-induced genetic and epigenetic changes, 2) improve hematologic and immune competence and health of cancer patients and survivors, and 3) improve cancer treatment outcomes. Moreover, identified and confirmed causative genetic and epigenetic changes that alter function of and are detectable in HSPCs and immune cells of mice will be evaluated as potential biomarkers for functional impairment of specific hematopoietic and immune cell types, which could be detected by genetic and epigenetic analysis of the peripheral blood leukocytes.