Reversing epithelial-mesenchymal transition in metastatic cancer cells using engineered nanomaterials and a mild photothermal effect

使用工程纳米材料和温和的光热效应逆转转移性癌细胞的上皮间质转化

• 批准号: 10514841
• 负责人: Congzhou Wang
• 金额: $ 41.35万
• 依托单位: SOUTH DAKOTA SCHOOL OF MINES AND TECHN'Y
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514841
• 关键词: 3-Dimensional; Actins; Antibodies; Antineoplastic Agents; Atomic Force Microscopy; Biocompatible Materials; Biological Assay; Biomedical Engineering; Biomedical Research; Biophotonics; Breast; Breast Cancer Cell; Cell Line; Cells; Cellular Morphology; Characteristics; Chemoresistance; Clinic; Complement; Cytokeratin; Cytoplasm; Cytoskeleton; Development; Disseminated Malignant Neoplasm; Dissociation; Dose; Drug resistance; E-Cadherin; Effectiveness; Engineering; Ensure; Epithelial; Event; Excision; Fluorescence Microscopy; Foundations; Future; Generations; Guanine Nucleotides; Guanosine Triphosphate; Health Sciences; Hyperthermia; Interruption; Knowledge; Lasers; Link; MCAM gene; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Mediating; Melanoma Cell; Membrane; Mesenchymal; Metastatic Prostate Cancer; Modeling; Molecular; N-Cadherin; Neoplasm Metastasis; Normal Cell; Operative Surgical Procedures; Pharmaceutical Preparations; Phase; Phenotype; Phosphorus; Phosphorylation; Play; Prevention; Process; Prostate; Research; Research Activity; Resolution; Role; Schools; Series; South Dakota; Specificity; Students; System; Technology; Testing; Therapeutic; Translations; Up-Regulation; Vimentin; Western Blotting; Work; anticancer treatment; base; cancer cell; cancer stem cell; cancer therapy; cancer type; career; cell motility; cell type; cellular targeting; chemotherapy; cytotoxicity; density; design; effectiveness evaluation; efficacy evaluation; ezrin; factor A; in vivo; innovation; melanoma; migration; moesin; mortality; nanomaterials; nanomechanics; nanosheet; neoplastic cell; overexpression; prevent; prostate cancer cell; radixin protein; recruit; rho; skills; stem-like cell; transcription factor; tumor; tumor progression; undergraduate research; undergraduate student; uptake; wound healing

Project Summary Tumor metastasis accounts for 90% of cancer-associated mortality. Epithelial-mesenchymal transition (EMT) of cancer cells provides the cancer cells with strong migratory-invasive abilities, and more recently, to mediate the development of chemoresistance, which is linked to cancer stem cell-like features. There is growing evidence suggesting that targeting EMT can be used as a therapeutic approach itself, or to enhance the efficacy of other anticancer treatments. However, the translation of EMT targeted compounds to the clinic has been challenging due to the lack of molecular-cellular targeting specificity and efficacy. Moreover, most of these compounds only focus on the prevention of EMT, but not on the tumor cells that have already undergone EMT. Innovations that are more specific, effective, and broadly applicable to eliminate EMT-type cancer cells with high metastatic capability and enhanced drug resistance hold great potential to revolutionize the treatment of tumor metastasis. In this project, we will develop a biomaterial-based approach to reverse the EMT of cancer cells by targeting a transmembrane EMT inducer, CD146, using engineered black phosphorus nanosheets (BPNs) and a mild photothermal effect. Our central hypothesis is that CD146 targeted BPNs and a mild hyperthermia will synergistically reverse the EMT in cancer cells, and thus stop the cancer cell migration and sensitize the cancer cells to classical chemotherapy drugs. Our preliminary studies have been able to demonstrate this approach in reversing the EMT of breast cancer cells, leading to nearly stopped cancer cell migration. As CD146 is overexpressed on a series of metastatic cancer cells, we will extend this approach to two other cancer types (including prostate cancer and melanoma), and uncover its working mechanism, which will lay the foundation for the next phase in vivo studies. Three aims have been set to test the hypothesis. Aim 1 will synthesize, optimize, and characterize CD146 targeted BPNs, and evaluate the approach based on CD146 targeted BPNs and a mild hyperthermia for the inhibition of cancer cell migration. Aim 2 will evaluate the efficacy of this approach in reversing the EMT process in cancer cells and the effectiveness of this approach in sensitizing the cancer cells to classical chemotherapeutics. Aim 3 will elucidate the molecule mechanism of how this approach reverses the EMT process in cancer cells. The proposed research is transformative in that (i) it will offer a new perspective for treating cancers by eliminating EMT-type cancer cells and minimizing their invasiveness and chemoresistance; and (ii) the mechanistic knowledge generated by this work will inform the future design of biophotonic nanomaterials to modulate cell phenotypes for in vivo cancer treatment and beyond. This research will also strengthen undergraduate research activities in biomedical engineering at the South Dakota School of Mines and Technology by recruiting nine undergraduate students into the proposed research (three for each year). Students will gain substantial knowledge and skills in biomedical research, which will prepare the students for a successful career in biomedical and health sciences.

项目摘要 肿瘤转移占癌症相关死亡率的90%。上皮-间质转化（EMT） 癌细胞为癌细胞提供了强大的迁移-侵袭能力，最近，介导了 化疗耐药性的发展，这与癌症干细胞样特征有关。越来越多的证据 这表明靶向EMT本身可以作为一种治疗方法，或提高其他治疗方法的疗效。 抗癌治疗然而，将EMT靶向化合物转化为临床一直具有挑战性 这是由于缺乏分子-细胞靶向特异性和功效。此外，这些化合物中的大多数仅 重点是预防EMT，而不是已经发生EMT的肿瘤细胞。的创新 更特异、有效和广泛适用于消除具有高转移性的EMT型癌细胞， 能力和增强的耐药性具有巨大的潜力来彻底改变肿瘤转移的治疗。 在这个项目中，我们将开发一种基于生物材料的方法，通过靶向肿瘤细胞的EMT来逆转癌细胞的EMT。 跨膜EMT诱导剂，CD 146，使用工程黑磷纳米片（BPN）和温和的 光热效应我们的中心假设是，CD 146靶向BPN和轻度热疗将 协同逆转癌细胞中的EMT，从而阻止癌细胞迁移并使癌症敏化 细胞与传统化疗药物的反应。我们的初步研究已经能够证明这种方法， 逆转乳腺癌细胞的EMT，导致癌细胞迁移几乎停止。因为CD 146是 在一系列转移性癌细胞上过度表达，我们将把这种方法扩展到另外两种癌症类型。 （包括前列腺癌和黑色素瘤），并揭示其工作机制，这将为 下一阶段的体内研究。为了检验这一假设，设定了三个目标。目标1将综合，优化， 并表征CD 146靶向BPN，并基于CD 146靶向BPN和轻度 用于抑制癌细胞迁移的热疗。目标2将评估这种方法在以下方面的有效性： 逆转癌细胞中的EMT过程以及这种方法在敏化癌细胞中的有效性 到传统的化疗药物。目的3将阐明这种方法如何逆转 癌细胞的EMT过程。拟议的研究是变革性的，因为（i）它将提供一个新的视角 用于通过消除EMT型癌细胞并使其侵袭性最小化来治疗癌症， 化学抗性;和（ii）这项工作产生的机械知识将告知未来的设计 生物光子纳米材料用于调节细胞表型，用于体内癌症治疗及其他。本研究 还将加强南达科他州生物医学工程学院的本科生研究活动。 矿业和技术通过招募九名本科生进入拟议的研究（三个为每个 年）。学生将获得大量的生物医学研究知识和技能，这将为学生做好准备 在生物医学和健康科学方面取得成功的职业生涯。