Role of CD44 in adaptive plasticity of pancreatic cancer

CD44在胰腺癌适应性可塑性中的作用

• 批准号: 8925205
• 负责人: James W. Freeman
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8925205
• 关键词: Address; Adenocarcinoma Cell; Adverse effects; Antibodies; Biological Markers; Biology; CD44 Antigens; CD44 gene; Cancer Cell Growth; Cell Line; Cells; Data; Down-Regulation; Engraftment; Environment; Epithelial; Excision; Exons; Flow Cytometry; Gene Expression; Genetic Transcription; Growth; Homing; Hyaluronan; Hypoxia; Immigration; Immunoglobulin Class Switching; Integral Membrane Protein; Kinetics; Knowledge; Laboratories; Lead; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metastatic Lesion; Micrometastasis; Modeling; Molecular; Neoplasm Metastasis; Pancreatic Ductal Adenocarcinoma; Patients; Phenotype; Play; Population; Process; Property; Protein Isoforms; Proteins; Proteoglycan; RNA Splicing; Reporting; Research; Resistance; Resistance development; Role; Signal Transduction; Site; Snails; Stem cells; Stress; Stromal Cells; Switch Genes; Testing; Transcription Repressor/Corepressor; Treatment Efficacy; Variant; base; cancer cell; cancer stem cell; chemotherapy; epithelial to mesenchymal transition; gemcitabine; improved; in vivo; insight; malignant breast neoplasm; mouse model; neoplastic cell; outcome forecast; pancreatic cancer cells; phrases; prevent; public health relevance; response; small hairpin RNA; therapy resistant; tumor; tumor progression

 DESCRIPTION (provided by applicant): Adaptive plasticity is a phrase used to explain how cancer cells gain selective growth and survival capabilities through phenotypic changes in response to their environment. Adaptive plasticity is exemplified by epithelial to mesenchymal transition (EMT) a process, which enables cancer cells to become migratory and invasive as well as having an increase in survival properties. This process can be reversed to a mesenchymal to epithelial transition (MET), which is believed to favor tumor engraftment and growth of cancer cells at metastatic sites. EMT in cancer cells is linked with isoform switching of the transmembrane protein CD44 from expressing the CD44 variant isoform (CD44v) to expressing CD44 standard form (CD44s). In this context we found that treatment of BxPC3 pancreatic ductal adenocarcinoma (PDAC) cell line with gemcitabine induces EMT and a high level of expression of CD44s with a decrease in expression of CD44v isoforms. This suggests that an adverse effect of chemotherapy may drive EMT, enhancing invasiveness and rendering tumor cells more resistant to chemotherapy. Moreover, we were able to use flow cytometry to select out from a PDAC cell lines (CFPAC-1 and AsPC1) a subpopulation of cells expressing high levels of CD44s. Knockdown of CD44s, in these cells, caused them to undergo MET, to be less invasive and to become more responsive to chemotherapy. These studies suggest that chemotherapy or other environmental stresses may induce a CD44s phenotype that promotes survival and is more invasive; however optimal tumor regrowth following chemotherapy or growth after engraftment of micrometastases may require re-switching to a CD44v phenotype and down regulation of CD44s expression. We hypothesize that CD44s and its variant isoforms are key regulators of adaptive plasticity in pancreatic cancer cells. We further hypothesize that understanding the molecular basis for adaptive plasticity will provide new strategies for improving therapy. These studies represent new data from our laboratory and build on 20 years of research solely focused on the biology and treatment of pancreatic cancer. To address these hypotheses we propose the following three objectives. Objective 1. Determine the functional relevance of CD44s and CD44v in PDAC. This objective will be addressed using isogenic matched cell line models in which expression of CD44s and CD44v isoforms are regulated. The effects on modulating expression of CD44v and CD44s will be assessed for phenotype, invasiveness, response to chemotherapy, tumor engraftment and growth. Objective 2. Determine the mechanism(s) that regulates CD44 isoform switching and CD44 expression. This objective will determine the potential role of EMT related transcriptional repressors Snail and Zeb1 in suppressing ESRP1 that is required for expression of CD44v isoforms and further identify the mechanisms that lead to the increased transcription of CD44s. Objective 3. Determine whether anti-CD44 antibody prevents CD44 isotype switching or expression level and whether this improves response to chemotherapy and reduces metastasis. These studies will provide important new insights related to adaptive plasticity and determine whether this knowledge can be used to counter act adverse effects of chemotherapy induced phenotypic switching. Inhibiting or reversing the switch towards an EMT phenotype may prove to be an important strategy for increasing the response to chemotherapy and patient survival.

 描述（由申请人提供）： 适应性可塑性是一个短语，用于解释癌细胞如何通过响应环境的表型变化获得选择性生长和生存能力。适应性可塑性的例子是上皮间质转化（EMT）过程，该过程使癌细胞能够迁移和侵袭。并且具有增加的存活特性，该过程可以逆转为间充质到上皮细胞的转变（MET），这被认为有利于肿瘤的植入和生长。癌细胞中的 EMT 与跨膜蛋白 CD44 从表达 CD44 变异异构体 (CD44v) 到表达 CD44 标准形式 (CD44s) 的异构体转换有关。 (PDAC) 细胞系与吉西他滨诱导 EMT 和 CD44s 高水平表达，同时 CD44v 表达减少这表明化疗的副作用可能会促进 EMT，增强侵袭性并使肿瘤细胞对化疗更具抵抗力。此外，我们能够使用流式细胞术从 PDAC 细胞系（CFPAC-1 和 AsPC1）中筛选出 a。这些细胞中表达高水平 CD44 的细胞亚群导致它们接受 MET，侵袭性更小，并且对化疗或其他环境应激更加敏感。可能会诱导促进生存且更具侵袭性的 CD44s 表型；然而，化疗后或微转移植入后的最佳肿瘤再生可能需要重新转换为 CD44v 表型并下调 CD44s 表达。我们进一步追求了解适应性可塑性的分子基础将为改善治疗提供新的策略。为了解决这些假设，我们提出了以下三个目标：确定 CD44s 和 CD44v 在 PDAC 中的功能相关性。等基因匹配细胞系模型，其中 CD44s 和 CD44v 亚型的表达受到调节，将评估对 CD44v 和 CD44s 表达的调节作用的表型、侵袭性、反应。目标 2. 确定调节 CD44 异构体转换和 CD44 表达的机制 该目标将确定 EMT 相关转录抑制因子 Snail 和 Zeb1 在抑制 ESRP1 表达方面的潜在作用。 CD44v 亚型并进一步确定导致 CD44 转录增加的机制 目标 3. 确定抗 CD44 抗体是否可以阻止 CD44。同种型转换或表达水平，以及这是否会改善对化疗的反应并减少转移，这些研究将提供与适应性可塑性相关的重要新见解，并确定这些知识是否可用于抵消化疗引起的表型转换的不利影响。转向 EMT 表型可能被证明是提高化疗反应和患者生存率的重要策略。