The role of wild-type KRAS in the context of tumor profession and metastasis

野生型 KRAS 在肿瘤发生和转移中的作用

• 批准号: 9047247
• 负责人: Gloria Huei-Ting Su
• 金额: $ 43.65万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047247
• 关键词: 12p; Address; Alleles; Attention; Cancer Patient; Cancer cell line; Cell Lineage; Cells; Chromosomes; Clonal Expansion; Colon Carcinoma; Colorectal; Colorectal Cancer; Data; Development; Doxycycline; Fluorescence; Frequencies; Future; Gene Expression; Gene Targeting; Genes; Genetic; Genetically Engineered Mouse; Genome Scan; Genotype; Goals; Growth; Harvest; Health; Histologic; Human; Human Cell Line; In Vitro; Incidence; KRAS2 gene; Label; Lead; Learning; Lesion; Loss of Heterozygosity; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Measures; Membrane; Methods; Modeling; Molecular; Molecular Profiling; Mus; Mutate; Neoplasm Metastasis; Oncogenes; Oncogenic; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Patient Care; Patients; Pilot Projects; Premalignant; Primary Neoplasm; Prognostic Marker; Publications; RNA; Reporting; Resected; Role; SNP array; Sampling; Serum; Siblings; Signal Pathway; Signal Transduction; Site; Specimen; Staging; Study models; System; Testing; Tetanus Helper Peptide; Tumor Burden; Tumor Suppressor Genes; Tumor Suppressor Proteins; Visual; anticancer research; arm; cancer cell; cancer genetics; cancer type; cell type; design; differential expression; functional outcomes; genetic profiling; in vivo; innovation; mouse model; mutant; neoplastic cell; next generation; novel; novel therapeutics; panacea; pancreatic cancer cells; pancreatic neoplasm; pancreatic tumorigenesis; restoration; success; targeted treatment; therapeutic target; therapy development; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): KRAS is a major oncogene for pancreatic (>90%), colorectal (>40%), and lung cancers (>16%); three cancer types that are responsible for 23% of cancer incidence and 43% cancer. Naturally, concerted efforts have focused on developing therapies against oncogenic KRAS- inhibition of KRAS expression, membrane association, effector signaling pathways, etc. However, success has been limited over the past 30 years. Although these past strategies have failed for diverse reasons, one commonality is that they target both the wild-type (WT) and oncogenic forms of KRAS. Our recent publication reported that increased loss of the WT-KRAS allele in the presence of oncogenic KRAS is associated with pancreatic cancer metastasis in both human samples and mouse modeling. We have also demonstrated that restoration of WT-KRAS expression in pancreatic cancer cells reduced cancer cell invasiveness in vitro and in vivo. These findings challenge the canonical view of KRAS functions and prompted us to hypothesize that the WT- KRAS may serve as a tumor-suppressor gene in metastasis in the presence of mutant KRAS. To-date, little attention has been bestowed on the function of WT-KRAS in the context of cancer. To test our hypothesis, in Aim 1, we will investigate if the loss of the WT-Kras allele in pancreatic cancer cells with mutant Kras would increase tumor burden and/or metastasis in vivo. In Aim 2, we will investigate if the restoration of WT-Kras expression will suppress pancreatic tumor progression and metastasis in vivo. Aim 3, we will generate differential molecular profiles between pancreatic cancer cells with Krasmt/wt and Krasmt/- genotypes and investigate the translational values of these differentially expression genes. The innovations here include: 1) We will employ in vivo multi-fluorescence labeling systems to differentially label pancreatic cancer cells that possess mutant Kras with or without WT-Kras. We will trace these differentially fluorescence-labeled cancer cells in mice as the tumors progress to metastasis, in both visual and quantitative manners. 2) The complementary designs of Aim 1 and Aim 2 (to evaluate the loss or restoration of WT-Kras on tumor progression and metastasis in vivo) will stringently test our hypothesis that the WT-Kras is involved in metastasis. 3) Finally, the identification of differentially expressed genes in Aim 3 wll not only provide the molecular mechanisms for the observed phenotypic differences between Krasmt/wt and Krasmt/- pancreatic cancer cells, but also potential prognostic markers and new gene targets for the next generation of KRAS target therapies that will distinguish between WT and mutant KRAS signaling. Although we cannot be certain that the ability for a new therapeutic to discriminate between WT and mutant KRAS will be the panacea for KRAS target therapies. Nevertheless, the potential role of WT-KRAS in cancer metastasis has to be addressed and may have profound impacts on future cancer research and patient care.

 描述（由申请人提供）：KRAS是胰腺癌（>90%）、结直肠癌（>40%）和肺癌（>16%）的主要致癌基因;三种癌症类型占癌症发病率的23%和43%。自然，一致的努力集中在开发针对致癌KRAS的疗法-抑制KRAS表达、膜结合、效应信号通路等。然而，在过去30年中，成功有限。尽管这些过去的策略由于各种原因而失败，但一个共同点是它们靶向KRAS的野生型（WT）和致癌形式。我们最近的出版物报道，在致癌KRAS存在的情况下，WT-KRAS等位基因的丢失增加与人类样本和小鼠模型中的胰腺癌转移相关。我们还证明了胰腺癌细胞中WT-KRAS表达的恢复降低了体外和体内癌细胞的侵袭性。这些发现挑战了KRAS功能的经典观点，并促使我们假设WT-KRAS可能在突变KRAS存在下在转移中充当肿瘤抑制基因。迄今为止，很少有人关注WT-KRAS在癌症背景下的功能。为了验证我们的假设，在目的1中，我们将研究在具有突变型Kras基因的胰腺癌细胞中WT-Kras等位基因的缺失是否会导致胰腺癌细胞中WT-Kras基因的缺失。 Kras在体内会增加肿瘤负荷和/或转移。在目标2中，我们将研究WT-Kras表达的恢复是否会抑制体内胰腺肿瘤的进展和转移。目的3：建立Krasmt/wt和Krasmt/-基因型胰腺癌细胞的差异表达基因谱，并研究这些差异表达基因的翻译价值。这方面的创新包括：1）我们将采用体内多荧光标记系统来差异标记具有突变Kras（具有或不具有WT-Kras）的胰腺癌细胞。我们将在小鼠中追踪这些差异荧光标记的癌细胞，因为肿瘤进展到转移，以视觉和定量的方式。2)目的1和目的2的互补设计（以评估体内肿瘤进展和转移中WT-Kras的丢失或恢复）将严格检验我们的假设，即WT-Kras参与转移。3)最后，Aim 3中差异表达基因的鉴定将不仅为观察到的Krasmt/wt和Krasmt/-胰腺癌细胞之间的表型差异提供分子机制，而且还为下一代KRAS靶向治疗提供潜在的预后标志物和新的基因靶标，其将区分WT和突变型KRAS信号传导。虽然我们不能确定新的治疗方法区分WT和突变型KRAS的能力是否是KRAS靶向治疗的灵丹妙药。尽管如此，WT-KRAS在癌症转移中的潜在作用仍有待解决，并可能对未来的癌症研究和患者护理产生深远的影响。