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

描述（由申请方提供）：手术切除是胰腺导管腺癌（PDAC）的唯一治愈性治疗方法，但禁忌用于疾病已转移的患者。提高治愈率的选择包括转移性细胞群的早期检测和/或有效治疗靶向。根据定义，所有转移性癌症必须能够逃离原发肿瘤部位，在循环系统内存活，并在继发部位植入和增殖。目前，体外系统不能充分模拟迁移细胞从肿瘤穿过循环系统时所经历的变化的微环境。该项目是癌症生物化学家和生物医学工程师之间的合作项目，旨在开发一种“PDAC-on-a-chip”，重现肿瘤和循环环境中的氧气环境。因此，该装置能够分离需要靶向治疗的侵袭性肿瘤细胞的部分。“肿瘤区室”中的细胞将暴露于体内样慢性或间歇性循环缺氧，其触发细胞运动。运动细胞可以穿透凝胶屏障并“渗透” 进入模拟肿瘤血管或淋巴系统的二级富氧“循环室”。侵袭性细胞经历的氧休克进一步选择可能等同于体内观察到的循环肿瘤细胞的循环存活细胞。在转移性癌症中，这种循环细胞群还必须含有至少一种癌症干细胞。由于间歇性缺氧被认为是触发上皮-间充质转化的关键因素，而上皮-间充质转化与干细胞生成/选择和治疗抗性有关，因此PDAC芯片提供了一种分离干细胞富集群体的新方法。据我们所知，这是唯一一种调节培养条件以选择/产生和收集与在细胞培养中观察到的循环癌细胞群相当的细胞的体外装置。 vivo.该设备将用于收集细胞，以无偏地鉴定转移性癌症和胰腺癌干细胞的标志物。这些标志物的鉴定可用于筛选侵袭性PDAC的患者样本，并最终为治疗开发提供靶点。在多路复用格式中，该装置还可用于筛选抗转移和/或抗癌干细胞疗法。 公共卫生相关性：胰腺肿瘤中缺氧的存在与患者预后不良相关。拟议项目的重点是开发更好的肿瘤缺氧和转移体外模型。这项新技术将改善细胞毒性和抗转移药物的筛选，帮助寻找新的治疗靶点，并有助于识别侵袭性癌症的相关生物标志物。总体目标是改善胰腺癌患者的治疗结果。

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. PUBLIC HEALTH RELEVANCE: The presence of hypoxia in pancreatic tumors is correlated with poor patient outcome. The proposed project focuses on the development of better in vitro models of tumor hypoxia and metastasis. This new technology will improve the screening of cytotoxic and antimetastatic agents, help find new targets for therapy and aid in the identificatio of relevant biomarkers for aggressive cancer. The overall objective is to improve treatment outcome in pancreatic cancer patients.