PDAC-on-a-Chip for Selection of Aggressive, Therapy-Resistant Tumor Cells

用于选择侵袭性、治疗耐药性肿瘤细胞的 PDAC 芯片

• 批准号: 8518272
• 负责人: MICHAEL GAMCSIK
• 金额: $ 7万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518272
• 关键词: Address; Adenocarcinoma Cell; Antimetastatic Agent; Biological Assay; Biological Markers; Biomedical Engineering; Blood Circulation; Blood Vessels; CD44 gene; Cancer Patient; Cancer cell line; Cardiovascular system; Cell Count; Cell Culture Techniques; Cell Survival; Cells; Characteristics; Chronic; Collecting Cell; Cytotoxic agent; Data; Development; Devices; Diagnosis; Disease; Disseminated Malignant Neoplasm; Early Diagnosis; Elements; Environment; Epithelial; Excision; Gases; Gel; Generations; Genetic; Harvest; Hypoxia; Implant; In Situ; In Vitro; Invaded; Laboratories; Link; Lymphatic System; MMP2 gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Mesenchymal; Metabolic; Methods; Microfabrication; Microfluidics; Modeling; Molecular; Neoplasm Circulating Cells; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Operative Surgical Procedures; Outcome; Oxidative Stress; Oxygen; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Pattern; Play; Population; Primary Neoplasm; Proliferating; Proteomics; Resistance; Sampling; Shock; Site; Staging; Stem cells; Survival Rate; System; Technology; Therapeutic; Time; Tissues; Travel; Treatment outcome; Variant; aggressive therapy; cancer stem cell; cell growth; cell motility; circulating cancer cell; clinically relevant; experience; improved; in vitro Model; in vivo; metastatic process; molecular marker; mortality; neoplastic cell; new technology; novel strategies; pancreatic neoplasm; response; screening; stem cell therapy; therapeutic target; therapy development; therapy resistant; tumor

DESCRIPTION (provided by applicant): Surgical resection is the only curative therapy for pancreatic ductal adenocarcinoma (PDAC) but is contraindicated in patients in which the disease has metastasized. Options to improve curative rates include earlier detection and/or effective therapeutic targeting of the metastatic cell population. By definition, all metastatic cancers must be able to escape the primary tumor site, survive within the circulatory system and implant and proliferate in a secondary site. Currently, in vitro systems cannot adequately mimic the changing microenvironments a migrating cell experiences as it travels from the tumor and through the circulatory system. This project is a collaborative venture between a cancer biochemist and a biomedical engineer to develop a 'PDAC-on-a-chip' that recreates the oxygen environments found both in the tumor and circulatory environment. This device, therefore, is capable of isolating the fraction of aggressive tumor cells that needs to be targeted for therapy. Cells in the 'tumor compartment' will be exposed to in vivo-like chronic or intermittent, cycling hypoxia that triggers cell motility. The motile cells can penetrate a gel barrier and 'intravasate' into a secondary oxygen-rich 'circulatory compartment' that mimics the tumor blood vessel or lymphatic system. The oxygen shock experienced by invasive cells further selects for circulation-viable cells likely equivalent to the circulating tumor cells observed in vivo. In metastatic cancers, this circulating cell population must also contain at least one cancer stem cell. Since intermittent hypoxia has been proposed as a key player in triggering the epithelial-mesenchymal-transition that is involved with stem cell generation/selection and therapy resistance, the PDAC-on-a-chip offers a new way to isolate stem cell-enriched populations. As far as we are aware, this is the only in vitro device that modulates culture conditions to select/generate and collect cells equivalent to the circulating cancer cell populations observed in vivo. This device will be used to collect cells for the unbiased identification of markers of metastatic cancer and pancreatic cancer stem cells. Identification of these markers could be used to screen patient samples for aggressive PDAC and ultimately provide targets for therapy development. In multiplexed format, this device could also be used to screen for anti-metastic and/or anti-cancer stem cell therapies.

描述（由申请人提供）：手术切除是胰腺导管腺癌（PDAC）的唯一治疗疗法，但在疾病转移的患者中是禁忌的。提高治疗率的选择包括转移细胞群的早期检测和/或有效的治疗靶向。根据定义，所有转移性癌症都必须能够逃脱原发性肿瘤部位，在循环系统中生存，并在次要部位植入和增殖。目前，体外系统无法充分模仿微环境变化的细胞体验，因为它从肿瘤传播并通过循环系统。该项目是癌症生物化学家和生物医学工程师之间的合作企业，用于开发“芯片上的PDAC-a-A-Chip”，从而重现在肿瘤和循环环境中发现的氧气环境。因此，该装置能够分离需要针对治疗的侵袭性肿瘤细胞的比例。 “肿瘤区室”中的细胞将暴露于体内样慢性或间歇性的循环缺氧，这会触发细胞运动。运动细胞可以穿透凝胶屏障并“静脉内” 进入模仿肿瘤血管或淋巴系统的二氧化氧气隔室。侵入性细胞经历的氧休克进一步选择了可行的可行细胞，可能等同于体内观察到的循环肿瘤细胞。在转移性癌症中，这种循环的细胞群还必须至少包含一个癌细胞。由于已经提出间歇性缺氧是触发与干细胞产生/选择和耐药性有关的上皮 - 间质转换的关键参与者，因此PDAC-A-A-CHIP提供了一种新的方法来分离干细胞增强群体。据我们所知，这是唯一调节培养条件选择/生成和收集相当于循环癌细胞种群的细胞的体外装置 体内。该装置将用于收集细胞，以无偏向转移性癌症和胰腺癌干细胞的标记。这些标记物的识别可用于筛选患者样品的侵略性PDAC，并最终为治疗开发提供了靶标。以多路复用格式，该设备也可用于筛选抗 - 替代和/或抗癌干细胞疗法。

项目成果

Biocompatibility of Tygon® tubing in microfluidic cell culture.

Tygon® 管在微流体细胞培养中的生物相容性。

• DOI: 10.1007/s10544-015-9938-9
• 发表时间: 2015
• 期刊: Biomedical microdevices
• 影响因子: 2.8
• 作者: Jiang,Xiao;Jeffries,RexE;Acosta,MiguelA;Tikunov,AndreyP;Macdonald,JeffreyM;Walker,GlennM;Gamcsik,MichaelP
• 通讯作者: Gamcsik,MichaelP