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）：胰腺癌是所有与癌症有关的死亡的第四个主要原因。众所周知，很难诊断，并且治疗选择非常有限。胰腺导管腺癌（PDAC）占所有形式胰腺癌的80％以上。了解PDAC细胞生长和运动性是开发有效治疗PDAC的有效药物治疗剂的关键。迄今为止，大多数体外PDAC研究都在二维（2D）组织塑料培养皿（TCP）上进行了不自然僵硬（E> 1 GPA）。 2D表面的超高刚度不仅非自然地偏振附着的细胞，而且还会导致细胞的行为不同，这是由于异常的机械感应。 2D细胞培养技术在肿瘤细胞的研究中也不足，这些研究受到基质组织的高度影响（即，在三维（3D）肿瘤中发现了活化的胰腺星状星状细胞，这些肿瘤由活化的胰腺星状层状细胞沉积）。还认为脱木质与胰腺癌细胞进行通信，以促进肿瘤进展并阻碍药物的渗透和功效。尽管一些研究探索了3D矩阵的实用性，例如Matrigel（R），用于PDAC研究，但市售的矩阵在机械上较弱，并且包含可能混淆实验结果的不确定和不可控制的生化成分。我们的中心假设是，具有动态和模块化特性的合成肿瘤生态位可用于阐明细胞外基质（ECM）提示对PDAC细胞生长，形态发生和药物有效性的影响。为此，我们将开发合成水凝胶，可以通过与PDAC相关的范围内的细胞相容光暴露（365-430nm）来可逆地加强/软化。在AIM 1中，我们将开发创新的动态脱木质模拟水凝胶基质，以封装PDAC细胞（例如Panc-1，Colo-357和Aspc1），并研究其生长，形态发生和上皮 - 间质质质转换（EMT）。在AIM 2中，我们将独立和可逆地调节载有细胞水凝胶的生物物理和生化特性，以描绘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PDAC提供新的治疗选择。