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Defining the early stages of chemotherapy-exacerbated cancer colonization of the lung: A role for host-ATF3

Middleton, Justin David
http://rave.ohiolink.edu/etdc/view?acc_num=osu1594999911940819

Abstract Details

2020, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Modern chemotherapy can be effective in the total elimination of tumors in some cancers, but is now thought to have little benefit for many patients with early stage and low risk breast cancer. In metastatic breast cancer, chemotherapy is the standard of care, but the advanced nature of the disease limits the effectiveness of chemotherapy to increase overall survival. Why chemotherapy is less effective in certain circumstances is hotly debated. It has long been assumed that cancer cell-intrinsic attributes or clonal selection of resistant mutants were the main cause of chemoresistance. More recently, mounting evidence suggests that the effect of chemotherapeutic drugs on non-cancer host cells may play a significant role in limiting the effectiveness of chemotherapy, through both the generation of chemoresistance and through active promotion of cancer progression. We previously found that ATF3 in host cells (host-ATF3) promotes breast cancer metastasis following chemotherapy treatment in mouse models. Atf3 is a stress-inducible gene that is induced upon various disruptions to homeostasis, in many different cell types. In that earlier work, we found that chemotherapy promotes metastasis by increasing the release of cancer cells from the primary tumor and generating a more hospitable metastatic site, all in an ATF3-dependent manner. My dissertation projection is to investigate the mechansisms by which host-ATF3 contributes to the exacerbation of metastasis by chemotherapy. Specifically, I focus on the metastatic site – the lung in our model – and on the early stages of cancer cell arrival. Once cancer cells are disseminated from the primary tumor, they still need to adhere to the endothelium at a distant organ, enter the parenchyma, avoid cell death and proliferate in order to become metastases. This process is called colonization, and is mediated by immune cells and inflammatory factors. As chemotherapy is a large systemic stress, and stress-inducible Atf3 regulates many inflammatory genes, we hypothesized that modulation of the inflammatory response is a key mechanism by which host-ATF3 contribute to chemotherapy-exacerbated metastasis. In Chapter 1 of this dissertation, I will summarize the current knowledge about topics related to my dissertation, including, ATF3, breast cancer, chemotherapy and the role of myeloid cells in cancer progression. In Chapters 2 and 3, I present my findings that chemotherapy exacerbates cancer cell colonization of the lung. To test the effect of chemotherapy on colonization, I pre-treated WT and ATF3 KO mice with chemotherapeutic drugs or vehicle four days before cancer cell injection. In doing so, I found two separate phenomena that resulted in a chemotherapy-dependent increase in cancer cell colonization. Chapter 2 will deal with the early phase in which chemotherapy exacerbates cancer cell adhesion to blood vessels, while Chapter 3 will discuss ATF3-dependent changes in cancer cell extravasation and death, and the role of ATF3 in myeloid cells in these processes. Taken together, my work demonstrates a new role for host-ATF3 in cancer cell colonization, a devastating unintended detrimental effect of chemotherapy, and a new understanding for how ATF3 in myeloid cells – upon chemotherapy treatment – changes interactions between the immune system and cancer cells.
Tsonwin Hai, PhD (Advisor)
Sujit Basu, MD/PhD (Committee Member)
Kalpana Ghoshal, PhD (Committee Member)
James Jontes, PhD (Committee Member)
165 p.
Biology; Biomedical Research; Molecular Biology
cancer; metastasis; chemotherapy; stress; ATF3

Recommended Citations

Citations

  • Middleton, J. D. (2020). Defining the early stages of chemotherapy-exacerbated cancer colonization of the lung: A role for host-ATF3 [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1594999911940819

    APA Style (7th edition)

  • Middleton, Justin. Defining the early stages of chemotherapy-exacerbated cancer colonization of the lung: A role for host-ATF3. 2020. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1594999911940819.

    MLA Style (8th edition)

  • Middleton, Justin. "Defining the early stages of chemotherapy-exacerbated cancer colonization of the lung: A role for host-ATF3." Doctoral dissertation, Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1594999911940819

    Chicago Manual of Style (17th edition)

osu1594999911940819
159
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