Radiation-Induced Tumor Cell Migration

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PROJECT ABSTRACT The goal of this R01 diversity supplement is to support the continued development of Luis Soto, a Ph.D. student in the Stanford Cancer Biology doctoral program, as he completes his doctoral research and moves towards a career in biomedical research. Luis immigrated to the United States at age 12 and subsequently became a citizen, and is the first in his family to attend college as well as graduate school. His first generation student status as well as his Latino heritage makes him a unique addition to the biomedical research community. The parent awrd for which this supplement is requested is focused on understanding the mechanisms through which radiation modulates tumor cell migration and the clinical significance of this phenomenon in cancer therapy. Historically, the efficacy of radiation therapy has been quantified in terms of the number of cells killed within the irradiated field, with control and/or cure of the tumor being considered to occur when a certain number of logs of cell kill are achieved. However, it is increasingly recognized that radiation can exert secondary effects that can act both locally and systemically and may in part enhance or inhibit the killing of tumor cells by radiation. We have recently shown in both in vitro and in vivo systems that migrating circulating tumor cells (CTCs) that were outside the radiation field at the time of treatment and therefore unaffected by it can return to the parent lesion in a process that is stimulated by radiation. In our funded R01 project, we are studying this process using novel mouse models of radiotherapy and tumor cell migration, molecular analyses of radiation-induced granulocyte macrophage colony stimulating factor (GM-CSF), targeted therapies inhibiting this process, and analysis of blood samples collected from human cancer patients undergoing radiotherapy. The research to be conducted by Luis as part of this supplement will evaluate the radiation response of normal lung tissue, a site that commonly receives a moderate dose of radiation during treatments targeting lung, breast, and gastrointestinal tumors. Preliminary data collected by Luis has shown that the recruitment of CTCs to irradiated lung is increased, suggesting that radiation stimulates the attraction and/or growth of migrating tumor cells. Luis will apply novel mouse models of tumor cell migration and radiotherapy to study this process and to elucidate its molecular and cellular basis. He will then evaluate the ability of clinically-relevant therapies to inhibit this process, which could subsequently be combined with radiotherapy in the clinic to improve the efficacy of radiotherapy. This R01 supplement will therefore provide important basic knowledge concerning the secondary effects of radiation while furthering Luis’s development toward an independent investigator.