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Title:The impact of cholesterol and its metabolites on the ovarian tumor microenvironment and cancer progression
Author(s):He, Sisi
Director of Research:Nelson, Erik R
Doctoral Committee Chair(s):Nelson, Erik R
Doctoral Committee Member(s):Bagchi, Milan K; Roy, Edward; Smith, Andrew M
Department / Program:Molecular & Integrative Physl
Discipline:Molecular & Integrative Physi
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):cholesterol
CYP27A1
Abstract:There is an urgent need to develop new therapeutic or lifestyle strategies for treating ovarian cancer due to its high recurrence and mortality rate. In this regard, we and others have found that cholesterol appears to be clinically important for ovarian cancer survival, highlighting it and its metabolism as potential therapeutic targets for improving the lifespan of patients. In a cohort of 153 patients, we found high total, LDL or non-HDL cholesterol was associated with high tumor grade, which in turn was associated with increased likelihood of cancer spreading to secondary locations. Consistently, high HDL-C was protective as it was associated with early stage cancers and better progression-free survival (PFS). Patients prescribed cholesterol lowering drugs such as statins, cholesterol absorption inhibitors or fiber were associated with significantly improved overall survival (OS). In addition, prescriptions at least one year prior to diagnosis was associated with increased probability of low tumor grades. Cytochrome P450 enzymes catalyze the first steps in cholesterol metabolism pathways. Among them, CYP27A1 is highly expressed in myeloid cells and oxidizes cholesterol into 27-hydroxychoelsterol (27HC), which is the most abundant oxysterol and an endogenous signaling molecule. In addition, serum 27HC concentration closely correlates to that of cholesterol. Analysis of publicly available databases indicated that low tumoral CYP27A1 expression was associated with better progression-free survival and overall survival. Conversely, high tumoral CYP7B1 expression, the enzyme that metabolites 27HC, was associated with improved progression-free survival. Therefore, we hypothesized that CYP27A1/27HC might be mediating the effects of cholesterol on cancer survival. CYP27A1 deletion or exogenous 27HC had no effects on cancer cellular proliferation, however, we found ovarian tumors failed to grow in CYP27A1-/- mice, eventually completely regressing, while treatment with exogenous 27HC was able to sustain tumor growth in CYP27A1-/- mice, indicating that CYP27A1/27HC are important for ovarian cancer progression. Analysis of tumors and lymphoid tissues suggested that 27HC was associated with compromised immunosurveillance. Specifically, CYP27A1/27HC-axis altered the recruitment of 1) monocytic-MDSCs, an immunosuppressive subtype of myeloid cells, 2) antigen-presenting myeloid cells, and 3) CD4+ T cells. In addition, bone marrow from wildtype mice was able to sustain tumor growth in CYP27A1-/- mice, suggesting the effect of CYP27A1/27HC were mediated by bone marrow derived cells (e.g. myeloid cells). Thus, the CYP27A1/27HC-axis presents an alternative path for cancer associated immunosuppression, offering a potentially novel therapeutic target. We tested the therapeutic utility of targeting this axis and found that a small molecule CYP27A1 inhibitor significantly improved the efficacy of anti-PDL1 checkpoint inhibition in a preclinical model. Collectively, our data suggest that cholesterol/27HC-axis modulates the ovarian tumor microenvironment and promotes cancer progression, revealing a novel therapeutic target for the treatment of ovarian cancer.
Issue Date:2020-04-16
Type:Thesis
URI:http://hdl.handle.net/2142/108251
Rights Information:Copyright 2020 Sisi He
Date Available in IDEALS:2020-08-27
Date Deposited:2020-05


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