LBPO.TB01 · 肿瘤生物学 · Late-Breaking
构建乳腺脂肪-癌共培养模型以解析脂质异质性对三阴性乳腺癌的影响
Development of breast adipose-cancer co-culture model to decipher the impact of lipid heterogeneity on triple-negative breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
三阴性乳腺癌（TNBC）是一种高度侵袭性的乳腺癌亚型，占所有乳腺癌病例的10-15%。它还以对化疗的高度耐药和低生存率为特征。脂质组成和患者人口学特征（如肥胖）已与TNBC相关联，而肿瘤微环境（TME）中与肥胖相关的脂肪酸可驱动代谢性炎症并促进TNBC进展。尽管如此，TNBC亚型对TME内脂质组成的独特影响，及其随后作为TNBC细胞生长和疾病进展能量来源的作用，仍知之甚少。因此，解析TNBC的TME中的脂质异质性将为TNBC进展提供新见解，并最终揭示新的治疗靶点。我们协作团队的既往工作已证明，与匹配的正常组织相比，TNBC肿瘤中脂质呈异质性分布。此外，包括亚油酸（LA）和油酸（OA）在内的特定脂质种类有所增加。我们推测，富含LA和OA的独特TNBC脂质组成助长TNBC进展。为了在脂质组成背景下理解TNBC驱动的TME重塑的影响，我们通过将分化的乳腺脂肪来源ASC（BrASC）与TNBC共培养，开发了一个富含LA和OA的TNBC模型。我们证明，通过在向脂肪生成谱系分化期间用TNBC特有的脂肪酸处理BrASC，可以成功构建脂肪细胞-TNBC共培养模型；脂肪酸的产生和摄取通过定量BODIPY荧光显微镜得到确认。TNBC细胞活力通过定量荧光显微镜得到确认，可向系统中添加高达200 µM的脂质同时保持细胞活力。我们的结果表明，BrASC在脂肪生成分化过程中掺入外源性脂质，且这些BrASC与TNBC的共培养提供了脂质转移。总体而言，我们的结果表明，可以开发一种体外模型来探究异质性脂质对TNBC-TME的影响。未来研究将包括评估BrASC中脂质谱改变对TNBC进展的影响。总之，本研究的长期目标是开发一种体外工具以研究独特脂质TME对TNBC的影响，从而改进当前的TNBC临床前模型。
查看英文原文 English abstract
Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype accounting for 10-15% of all breast cancer cases. It is further characterized by high resistance to chemotherapy and low survival rates. Lipid composition and patient demographics, such as obesity, have been associated with TNBC, and obesity related fatty acids in the tumor microenvironment (TME) can drive metabolic inflammation and promote TNBC progression. Despite this, the unique impact of the TNBC subtype on lipid composition within the TME, and its subsequent role as an energy source for TNBC cell growth and disease progression, remains poorly understood. Therefore, deciphering the lipid heterogeneity in the TME of TNBC will provide novel insights into TNBC progression and ultimately unveil novel therapeutic targets. Prior work by our collaborative group has demonstrated a heterogeneous distribution of lipids across TNBC tumors compared to matched normal tissue. Further, there was an increase in distinct lipid species, including linoleic acid (LA) and oleic acid (OA). We hypothesized that the distinct TNBC lipid composition enriched in LA and OA fuels TNBC progression. To understand the impact of TNBC-driven TME remodeling in the context of lipid composition, we developed a model of TNBC enriched for LA and OA through the co-culture of differentiated breast adipose-derived ASCs (BrASC) and TNBC. We demonstrated that an adipocyte-TNBC co-culture model can be successfully constructed by treating BrASC with fatty acids distinct to TNBC during differentiation to adipogenic lineage; fatty acid production and uptake was confirmed with quantitative BODIPY fluorescence microscopy. TNBC cell viability was confirmed with quantitative fluorescence microscopy, and up to 200μM of lipid can be added to the system while retaining cell viability. Our results demonstrated that BrASC incorporated exogenous lipids during adipogenic differentiation, and the co-culture of these BrASC with TNBC provided lipid transfer. Overall, our results suggest that an i n vitro model can be developed to interrogate the impact of heterogeneous lipids on the TNBC-TME. Future studies will include evaluating the impact of an altered lipid profile in BrASC on TNBC progression. In conclusion, the long-term goal of this research is to develop an in vitro tool to study the impact of the unique lipid TME on TNBC, thus improving upon current pre-clinical models for TNBC.
利益披露 Disclosure
K. Salim, None..
E. Sheikh, None..
J. A. Belgodere, None..
B. M. Collins Burow, None..
V. H. Barnes, None..
M. R. Gartia, None..
M. E. Burow, None..
E. C. Martin, None.