Characterizing breast cancer invasion and proliferation when co-aggregated with adipocytes in multicellular spheroids created with a custom bioreactor to augment cell-cell connectivity.

当与多细胞球体中的脂肪细胞共聚集时，表征乳腺癌的侵袭和增殖，该多细胞球体是用定制生物反应器创建的，以增强细胞间的连接。

• 批准号: 10631032
• 负责人: Carlos Luna Lopez
• 金额: $ 11.18万
• 依托单位: CALIFORNIA STATE UNIVERSITY SAN MARCOS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631032
• 关键词: 3-Dimensional; Adipocytes; Adipose tissue; Affect; Animal Model; Antineoplastic Agents; Attention; Biological; Biological Assay; Bioreactors; Breast; Breast Cancer Cell; Breast Cancer cell line; Brown Fat; Cancer Biology; Cancer Model; Cancer cell line; Cell Aggregation; Cell Differentiation process; Cell Proliferation; Cell-Cell Adhesion; Cells; Cellular Spheroids; Chemicals; Chemoresistance; Coculture Techniques; Custom; Devices; ERBB2 gene; Environment; Epidemic; Exhibits; Gene Expression; Geometry; Goals; Grant; Growth; Heterogeneity; Human; In Vitro; Invaded; Kidney; Liquid substance; Literature; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Measures; Methods; Modeling; Modernization; Mus; Ovarian; Phenotype; Physiological; Procedures; Proliferating; Prostate; Research; Rodent; Surface; System; Technology; Testing; Therapeutic; Touch sensation; Tumor Cell Invasion; Tumor Promotion; Woman; adipocyte differentiation; anticancer research; cancer cell; cancer type; cell behavior; cell type; density; drug discovery; implantation; improved; in vivo; innovation; malignant breast neoplasm; migration; response; scaffold; self assembly; subcutaneous; three dimensional structure; three-dimensional modeling; tool; triple negative cancer; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; two-dimensional; vibration

Project Summary Breast cancer is the most common form of cancer in women and is considered a modern-day epidemic, especially because of the high degree of heterogeneity. Multiple studies have shown that the tumor microenvironment contributes to cancer growth and chemoresistance. Cancer-adipocyte interactions have gained increased attention as the crosstalk between them has been shown to promote tumor proliferation and increased cancer migration. However, the physiological relevance of previous co-culture methods is questionable. Several past studies did not use human cells, or differentiate between white and brown adipocytes, which have different phenotypes. In this proposal we will analyze tumor invasiveness of human triple negative and luminal A breast cancer cells when co-cultured with human brown and white adipocytes. To do this, we propose to use a 3D multicellular tumor spheroid system. Tumor spheroids provide a physiological relevant environment to study cancer biology and drug discovery. Compared to 2D paradigms, research shows 3D models better recapitulate chemoresistance and tumor growth found in human in vivo tumors. In the lab, we have developed a bioreactor that uses surface vibrations to produce Faraday waves that aggregate cells inside a liquid chamber. Devices with similar technology have been used to assemble scaffold-free 3D cell constructs and spheroids in a rapid and scalable way, without the need for additional chemicals or intrusive procedures. In this grant, we also seek to determine if this technology generates multicellular spheroids with greater cell-cell adhesion, compared to standard self-assembly. To achieve the scientific and technological goals of this grant, two specific aims are proposed: The first aim will compare the viability and connectivity of multicellular spheroids formed with our surface vibration bioreactor versus standard self-assembly spheroids. The second aim will measure changes in tumor invasiveness and proliferation in tumor spheroids made with human cancer cells and human adipocytes. We will compare two different types of breast cancer cells: triple negative and luminal A and two different types of adipocytes: white and brown adipocytes. These combinations will allow us to investigate the interactions of different cancer phenotypes with specific adipocyte cell types. Overall, the proposed research will have a major scientific and technological impact by expanding our understanding of breast cancer-adipocyte interactions and testing a technology that could deliver multicellular spheroids with improved intracellular connectivity in a scalable manner. This will significantly impact the field of cancer biology and therapeutics, as cancer-adipocyte associations have been observed in a multitude of tumors, including prostate, ovarian, and pancreatic cancer.

项目概要 乳腺癌是女性最常见的癌症形式，被认为是现代流行病， 特别是因为高度异质性。多项研究表明，肿瘤 微环境有助于癌症生长和化疗耐药性。癌症与脂肪细胞的相互作用 由于它们之间的串扰已被证明可以促进肿瘤增殖和 癌症迁移增加。然而，以前的共培养方法的生理相关性是 有疑问。过去的几项研究没有使用人类细胞，也没有区分白色和棕色 脂肪细胞具有不同的表型。在本提案中，我们将分析人类肿瘤的侵袭性 与人棕色和白色脂肪细胞共培养时的三阴性和管腔 A 乳腺癌细胞。到 为此，我们建议使用 3D 多细胞肿瘤球体系统。肿瘤球体提供了生理 研究癌症生物学和药物发现的相关环境。研究表明，与二维范式相比 3D 模型更好地再现了人类体内肿瘤中发现的化疗耐药性和肿瘤生长。在实验室里，我们 开发了一种生物反应器，利用表面振动产生法拉第波，将细胞聚集在内部 液体室。具有类似技术的设备已用于组装无支架 3D 细胞结构 以快速且可扩展的方式制备球体，无需额​​外的化学品或侵入性程序。在 这笔赠款，我们还试图确定这项技术是否能产生具有更大细胞数量的多细胞球体 与标准自组装相比，粘合力。为实现本次资助的科技目标， 提出了两个具体目标：第一个目标是比较多细胞的生存能力和连接性 使用我们的表面振动生物反应器形成的球体与标准自组装球体形成的球体。第二个 目标将测量人类癌症制成的肿瘤球体中肿瘤侵袭性和增殖的变化 细胞和人类脂肪细胞。我们将比较两种不同类型的乳腺癌细胞：三阴性和 管腔 A 和两种不同类型的脂肪细胞：白色和棕色脂肪细胞。这些组合将使我们 研究不同癌症表型与特定脂肪细胞类型的相互作用。总体而言， 拟议的研究将通过扩大我们的理解而产生重大的科学和技术影响 乳腺癌与脂肪细胞的相互作用并测试一种可以提供多细胞球体的技术 以可扩展的方式改善细胞内连接。这将对癌症生物学领域产生重大影响 和治疗，因为在多种肿瘤中观察到癌症-脂肪细胞关联，包括 前列腺癌、卵巢癌和胰腺癌。