PO.TB03.05 · 肿瘤生物学
脂肪细胞中的肾上腺素能信号驱动卵巢癌细胞侵袭
Adrenergic signaling in adipocytes drives ovarian cancer cell invasion
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
高级别浆液性癌（HGSC）是最常见且最致命的卵巢癌亚型。HGSC可起源于输卵管，并常转移至大网膜；因此，我们力求进一步阐明HGSC定植于大网膜所涉及的代谢串扰。通过将成像质谱（IMS）应用于HGSC细胞与大网膜外植体的共培养，我们能够在空间上解析所产生的化学物质，并鉴定出与非致瘤性共培养或单培养相比HGSC+大网膜培养所特有的分子。其中一种分子是肾上腺素，IMS揭示其由大网膜产生。据此我们假设，大网膜脂肪细胞中的自分泌肾上腺素信号释放脂肪酸，从而驱动肿瘤进展。为助力更深入的机制研究，我们采用了一种人前脂肪细胞系，该细胞系可在培养中形成球体并分化为成熟脂肪细胞。经IMS分析，脂肪细胞球体以及与HGSC的共培养均产生肾上腺素，证实了负责产生肾上腺素的大网膜细胞类型为脂肪细胞。将大网膜外植体和脂肪细胞球体用肾上腺素（10μM）或普萘洛尔（1μM）处理，并收集所产生的条件培养基。三种HGSC模型——MOE PTEN shRNA、OVCAR4和OVCAR8——用条件培养基处理，并通过Matrigel包被的Boyden小室测定其侵袭潜能。与对照相比，来自任一脂肪细胞来源的经普萘洛尔处理的条件培养基导致侵袭显著降低，而经肾上腺素处理的大网膜条件培养基则显著增加了MOE PTEN shRNA的侵袭。对处理过的脂肪细胞球体条件培养基进行的非靶向脂质组学发现，在肾上腺素和普萘洛尔处理的条件培养基之间存在差异调控的脂质种类，包括脂肪酰、固醇和N-酰基乙醇胺。目前的工作力求探究肾上腺素对固醇生物合成的影响，确定所鉴定的任何脂质种类是否足以驱动HGSC细胞侵袭，并鉴定诱导脂肪细胞中肾上腺素产生的上游HGSC信号。总体而言，我们力求拓展对大网膜转移微环境定植中关键信号以及肾上腺素在其中作用的理解。
查看英文原文 English abstract
High grade serous cancer (HGSC) is the most common and lethal ovarian cancer subtype. HGSC can arise from the fallopian tube and habitually metastasizes to the omentum; consequently, we seek to further elucidate the metabolic crosstalk involved in HGSC colonization of omentum. By applying imaging mass spectrometry (IMS) to co-cultures of HGSC cells and omental explants we are able spatially resolve the chemistry produced and identify molecules unique to the HGSC + omentum cultures as compared to non-tumorigenic co-cultures or monocultures. One such molecule is epinephrine which IMS reveals to be produced by the omentum. From this we hypothesize autocrine epinephrine signaling in omental adipocytes liberates fatty acids driving tumor progression. To aid in more mechanistic investigation a human, pre-adipocyte line which forms spheroids and differentiates to mature adipocytes in culture is employed. Analyzed by IMS adipocyte spheroids and co-cultures with HGSC produced epinephrine confirming an omental cell type responsible to be adipocytes. Omental explants and adipocyte spheroids were subjected to treatment with epinephrine (10μM) or propranolol (1μM) and the resulting conditioned media collected. Three HGSC models -MOE PTEN shRNA , OVCAR4, and OVCAR8- were treated with conditioned media and their invasive potential measured by Matrigel coated Boyden chamber. Propranolol treated conditioned media from either adipocyte source resulted in significantly decreased invasion compared to control while epinephrine treated omental conditioned media significantly increased MOE PTEN shRNA invasion. Untargeted lipidomics performed on treated adipocyte spheroid conditioned media has uncovered lipid species differentially regulated between the epinephrine and propranolol treated conditioned medias including fatty acyls, sterols, and N-acylethanolamides. Current work seeks to explore the impact of epinephrine on sterol biosynthesis, determine if any identified lipid species is sufficient to drive HGSC cell invasion, and identify an upstream HGSC signal inducing epinephrine production in the adipocytes. Overall, we seek to expand our understanding of signaling critical in colonization of the omental metastatic niche and the role of the epinephrine therein.
利益披露 Disclosure
M. A. Haughan,
AstraZeneca Other, Internship.
C. Grundmann, None..
H. J. Lusk, None..
L. M. Sanchez, None..
J. E. Burdette, None.