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Novel Insights into Dedifferentiated Liposarcoma Pathogenesis: Evaluating the Tumor-Promoting Role of IL6/GP130 Signaling via MDM2 Upregulation

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2018, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Understanding the pathobiological drivers of dedifferentiated liposarcoma (DDLPS) is imperative for efficacious therapies to eventuate. These adipocytic tumors are largely unresponsive to chemotherapy, rendering surgical excision the therapeutic mainstay. However, surgery often proves to be technically challenging and locoregional recurrence is frequent. Treatment strategies targeting the mouse double mutant 2 (MDM2):p53 axis demonstrated promise in the laboratory, but failed to translate into the clinical setting. This lack of response likely involves additional mechanisms beyond the MDM2:p53 nexus. The largely ineffectual treatment strategies of today point to the need for therapies developed based on an understanding of DDLPS biology beyond the MDM2:p53 interaction. It is therefore imperative to study unexplored mechanisms in the hopes resolving this gap of knowledge of DDLPS biology, which will hopefully result in the development of novel and effective treatment approaches for patients bearing DDLPS. The proclivity of these tumors to occur and reoccur in the high-fat retroperitoneum warrants investigating the setting created by adipose. Fat tissue has been historically recognized as a driver of disease development by secreting pro-inflammatory cytokines such as interleukin 6 (IL6). IL6 trans-signaling, in which IL6 cytokine binds to soluble IL6R (sIL6Ra) and activates glycoprotein 130 (GP130) signal transduction, may be critically involved in chronic diseases having an inflammatory component. Consequently, the overall goal of our study was to investigate the role of GP130 as a driver of DDLPS and to evaluate preadipocyte cells as potential IL6 sources. We observed high GP130 expression in DDLPS tumors and cell lines compared to normal tissue and preadipocyte cell controls. Activation of GP130 by IL6 (10 ng/mL) increased DDLPS growth, migration, and induced STAT1 and STAT3 phosphorylation. Moreover, GP130 signal transduction induced MDM2 expression three- and ten-fold in DDLPS cell lines Lipo246 and Lipo815, respectively. Loss of GP130 signaling decreased DDLPS tumor cell growth and MDM2 levels. Preadipocytes (PreAdip) were found to secrete higher levels of IL6 than DDLPS cell lines. Culturing DDLPS cells in the presence of PreAdip cells or in PreAdip-derived conditioned media increased tumor growth and proliferation; the pro-tumor effects of PreAdip CM were reduced with the use of anti-IL6 monoclonal antibody MAB206. Treatment with small molecule GP130 inhibitor SC144 reduced DDLPS growth in vitro and in vivo, decreased IL6-mediated GP130 activation of STAT1 and STAT3, and reduced MDM2 expression. PreAdip cells demonstrated tolerance to SC144 (EC50 = 6.332 uM). Taken together, these data suggest that preadipocytes may act as in situ sources of IL6 for retroperitoneal DDLPS, and that IL6 activation of GP130 may promote the DDLPS oncogenic phenotype via activation of STAT1 and STAT3, and upregulation of MDM2.
Raphael Pollock, MD, PhD (Advisor)
Denis Guttridge, PhD (Advisor)
Joanna Groden, PhD (Committee Member)
Amal Amer, MD, PhD (Committee Member)
James Chen, MD (Committee Member)
Terri Hessler, PhD (Committee Member)
146 p.

Recommended Citations

Citations

  • Zewdu, A. (2018). Novel Insights into Dedifferentiated Liposarcoma Pathogenesis: Evaluating the Tumor-Promoting Role of IL6/GP130 Signaling via MDM2 Upregulation [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu15320904714479

    APA Style (7th edition)

  • Zewdu, Abeba . Novel Insights into Dedifferentiated Liposarcoma Pathogenesis: Evaluating the Tumor-Promoting Role of IL6/GP130 Signaling via MDM2 Upregulation. 2018. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu15320904714479.

    MLA Style (8th edition)

  • Zewdu, Abeba . "Novel Insights into Dedifferentiated Liposarcoma Pathogenesis: Evaluating the Tumor-Promoting Role of IL6/GP130 Signaling via MDM2 Upregulation." Doctoral dissertation, Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu15320904714479

    Chicago Manual of Style (17th edition)