Adaptable hydrogel platform to study pancreatic cancer

用于研究胰腺癌的适应性水凝胶平台

• 批准号: 8759705
• 负责人: Chien-Chi Lin
• 金额: $ 16.97万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759705
• 关键词: Accounting; Adenocarcinoma Cell; Animals; Antineoplastic Agents; Apoptosis; Artificial Pancreas; Back; Biochemical; Biocompatible Materials; Biomimetics; Cancer Patient; Cell Culture Techniques; Cells; Cessation of life; Chemicals; Complex; Cues; Cultured Cells; Cyclodextrins; Deposition; Desmoplastic; Development; Devices; Diagnosis; Drug resistance; Encapsulated; Ensure; Epithelial; Ethylene Glycols; Exhibits; Extracellular Matrix; Gel; Goals; Growth; Hydrogels; In Situ; In Vitro; Integrin Binding; Lead; Ligands; Light; Malignant Neoplasms; Malignant neoplasm of pancreas; Mesenchymal; Modeling; Morphogenesis; Normal Cell; Pancreas; Pancreatic Ductal Adenocarcinoma; Penetration; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Physicians; Plastics; Process; Property; Research; Research Project Grants; Role; Scientist; Sulfhydryl Compounds; Surface; Survival Rate; Testing; Therapeutic; Tissue Engineering; Tissues; Tumor Tissue; Ultraviolet Rays; Visible Radiation; anticancer research; azobenzene; base; cancer cell; cell behavior; cell growth; cell motility; cis trans isomerization; clinically relevant; crosslink; design; drug efficacy; ethylene glycol; extracellular; improved; innovation; matrigel; mimetics; neoplastic cell; novel therapeutics; outcome forecast; pancreatic cancer cells; public health relevance; stellate cell; success; tissue culture; tumor; tumor progression; two-dimensional

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of all cancer-related death. It is notoriously difficult to diagnose and has very limited therapeutic options. Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 80% of all forms of pancreatic cancer. Understanding PDAC cell growth and motility is the key to developing effective drug therapeutics for treating PDAC. To date, most in vitro PDAC studies have been conducted on two dimensional (2D) tissue-culture plastic dishes (TCP) that are unnaturally stiff (E > 1 GPa). The ultrahigh stiffness of a 2D surface not only un-naturally polarizes the attached cells, but also causes the cells to behave differently due to abnormal mechano-sensing. 2D cell culture techniques are also inadequate in the study of tumor cells, which are highly influenced by the stromal tissues (i.e., desmoplasia, dense extracellular matrices deposited by activated pancreatic stellate cells) found in three-dimensional (3D) tumors. It is also believed that desmoplasia communicates with pancreatic cancer cells to promote tumor progression and to hinder drug penetration and efficacy. Although a few studies have explored the utility of 3D matrices, such as Matrigel(R), for PDAC research, the commercially available matrices are mechanically weak and contain ill-defined and un- controllable biochemical components that may confound the experimental results. Our central hypothesis is that a synthetic tumor niche with dynamically and modularly adaptable properties can be used to elucidate the influence of extracellular matrix (ECM) cues on the growth, morphogenesis, and drug efficacy in PDAC cells. Toward this end, we will develop synthetic hydrogels that can be reversibly stiffen/soften via cytocompatible light exposure (365-430nm) in a range relevant to PDAC. In Aim 1, we will develop innovative dynamic desmoplasia-mimetic hydrogel matrix to encapsulate PDAC cells (e.g., PANC-1, COLO-357, and ASPC1) and study their growth, morphogenesis, and epithelial-mesenchymal transition (EMT). In Aim 2, we will independently and reversibly modulate the biophysical and biochemical properties of cell-laden hydrogels in order to delineate the influence of various immobilized and soluble extracellular factors on PDAC cell fate processes. We will also reveal the influence of these critical factors on drug resistance in PDAC. The information obtained from this study will open new therapeutic options for treating the lethal PDAC.

描述（由申请人提供）：胰腺癌是所有癌症相关死亡的第四大原因。众所周知，它很难诊断，而且治疗选择也非常有限。胰腺导管腺癌 (PDAC) 占所有形式胰腺癌的 80% 以上。了解 PDAC 细胞的生长和运动是开发治疗 PDAC 的有效药物疗法的关键。迄今为止，大多数体外 PDAC 研究都是在非自然刚性 (E > 1 GPa) 的二维 (2D) 组织培养塑料皿 (TCP) 上进行的。二维表面的超高刚度不仅使附着的细胞不自然地极化，而且还会导致细胞由于异常的机械感应而表现出不同的行为。 2D 细胞培养技术在肿瘤细胞的研究中也存在不足，因为肿瘤细胞深受三维 (3D) 肿瘤中发现的基质组织（即结缔组织形成，由活化的胰腺星状细胞沉积的致密细胞外基质）的影响。人们还认为结缔组织增生与胰腺癌细胞沟通，促进肿瘤进展并阻碍药物渗透和功效。尽管一些研究探索了 3D 基质（例如 Matrigel(R)）在 PDAC 研究中的实用性，但市售基质机械性能较弱，并且含有不明确且不可控的生化成分，可能会混淆实验结果。我们的中心假设是，具有动态和模块化适应性特性的合成肿瘤生态位可用于阐明细胞外基质 (ECM) 线索对 PDAC 细胞生长、形态发生和药物疗效的影响。为此，我们将开发合成水凝胶，可以通过与 PDAC 相关的细胞相容性曝光（365-430nm）来可逆地硬化/软化。在目标 1 中，我们将开发创新的动态促结缔组织模拟水凝胶基质来封装 PDAC 细胞（例如 PANC-1、COLO-357 和 ASPC1），并研究它们的生长、形态发生和上皮间质转化 (EMT)。在目标 2 中，我们将独立且可逆地调节载有细胞的水凝胶的生物物理和生化特性，以描述各种固定和可溶性细胞外因子对 PDAC 细胞命运过程的影响。我们还将揭示这些关键因素对 PDAC 耐药性的影响。从这项研究中获得的信息将为治疗致命性 PDAC 开辟新的治疗选择。