Molecular Basis of ME2-mediated Tumor Suppression in Pancreatic Cancer

ME2 介导的胰腺癌肿瘤抑制的分子基础

基本信息

项目摘要

Project Summary: Early systemic dissemination, extraordinary local invasion, late diagnosis, and inadequate response to the existing chemotherapy contribute to poor prognosis for pancreatic cancer patients. There is an urgent need to identify novel therapies that would significantly improve survival in patients. While most pancreatic ductal adenocarcinomas have mutations in Kras, multiple other genetic alterations contribute to molecular oncogenesis and patient prognosis. These genetic lesions hold the key to novel personalized therapies for pancreatic cancer patients but remain poorly explored. Identifying novel personalized therapeutic combinations would be a significant advancement in combating PDAC. We and others identified a novel ME2 deletion as a passenger deletion with SMAD4 loss, which is prevalent in up to 30% of PDAC patients. By utilizing cell culture models, organoids, orthotopically-implanted mouse models, and patient-derived xenografts of pancreatic ductal adenocarcinoma with and without ME2-loss, we made the novel observation that ME2 has a direct negative impact on tumor growth and metastasis in pancreatic cancer. Here, we propose to investigate the molecular basis of ME2 loss-mediated oncogenesis in pancreatic cancer. By utilizing a series of unbiased high-throughput screening approaches, we have identified novel signaling alterations in pancreatic cancer cells due to ME2 loss. Hence, we will also investigate the effectiveness of blocking the signaling pathways induced by the ME2 loss that facilitate aggressiveness in pancreatic cancer. Such mechanisms potentially regulate tumor cell growth and invasiveness of low ME2-expressing tumor cells. Thus, our studies will facilitate the development of new and more effective treatments for pancreatic cancer. Our long-term goal is to determine the molecular basis of ME2 loss-mediated signaling that facilitates invasiveness and metastasis in pancreatic cancer. In the first aim, we will utilize genetically engineered mice models to investigate the impact of ME2 loss on pancreatic cancer initiation, progression, and metastasis. The second aim will investigate the molecular basis of ME2 loss-mediated aggressiveness in pancreatic cancer. Aim 3 will investigate the potential of personalized therapies for patients with ME2 loss by utilizing spontaneous models and patient-derived xenografts and evaluate biomarkers and molecular regulators of their efficacy. Collectively, the proposed studies employ an innovative and integrative approach to elucidate the molecular basis of ME2 loss-mediated tumor progression and may uncover additional personalized therapies and biomarkers of therapeutic efficacies for the treatment of aggressive pancreatic cancer.
项目概述:早期系统性播散,局部侵袭异常,诊断较晚,不充分 对现有化疗的反应导致胰腺癌患者预后不良。有一个 迫切需要确定能够显著提高患者存活率的新疗法。虽然大多数胰腺 导管腺癌有Kras突变,多个其他基因改变导致分子 肿瘤发生与患者预后。这些基因损伤是新的个性化治疗方法的关键 胰腺癌患者,但仍然很少被探索。确定新的个性化治疗组合 将是打击PDAC的一个重大进步。 我们和其他人发现了一种新的ME2缺失,这是一种带有Smad4缺失的乘客缺失,这种缺失很普遍 在高达30%的PDAC患者中。通过利用细胞培养模型,器官,原位移植的小鼠 有无ME2缺失的胰腺导管腺癌模型和患者来源的异种移植 新发现ME2对胰腺肿瘤生长和转移有直接负面影响 癌症。在此,我们建议研究ME2缺失介导的胰腺肿瘤发生的分子基础。 癌症。通过利用一系列无偏见的高通量筛选方法,我们已经确定了新的 ME2缺失导致胰腺癌细胞的信号变化。因此,我们还将调查其有效性 阻断由ME2缺失诱导的促进胰腺癌侵袭性的信号通路。 这些机制可能调节肿瘤细胞的生长和低表达ME2的肿瘤细胞的侵袭力。 因此,我们的研究将促进胰腺癌新的、更有效的治疗方法的开发。 我们的长期目标是确定ME2丢失介导的信号转导的分子基础 胰腺癌的侵袭和转移。在第一个目标中,我们将利用转基因小鼠 研究ME2缺失对胰腺癌发生、发展和转移的影响的模型。这个 第二个目的是研究ME2缺失介导的胰腺癌侵袭性的分子基础。目标 3将利用自发性来研究ME2缺失患者的个性化治疗的潜力。 模型和患者来源的异种移植,并评估其有效性的生物标记物和分子调节剂。 总的来说,拟议的研究采用了一种创新和综合的方法来阐明分子 ME2缺失介导的肿瘤进展的基础,并可能发现更多的个性化治疗和 侵袭性胰腺癌治疗效果的生物标志物。

项目成果

期刊论文数量(0)
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Pankaj Kumar Singh其他文献

Utilization of wastewater as nutrient media and biomass valorization in marine Chrysophytes- Chaetoceros and Isochrysis
废水作为营养介质的利用和海洋金藻植物-角毛藻和等鞭金藻的生物量增值
  • DOI:
    10.1016/j.ecmx.2020.100062
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Pankaj Kumar Singh;Raya Bhattacharjya;A. Saxena;Bharti Mishra;A. Tiwari
  • 通讯作者:
    A. Tiwari
Applications of lipid-engineered nanoplatforms in the delivery of various cancer therapeutics to surmount breast cancer
  • DOI:
    10.1016/j.jconrel.2022.05.034
  • 发表时间:
    2022-08-01
  • 期刊:
  • 影响因子:
    11.500
  • 作者:
    Ujala Gupta;Brojendra Nath Saren;Kedar Khaparkhuntikar;Jitender Madan;Pankaj Kumar Singh
  • 通讯作者:
    Pankaj Kumar Singh
Hyperplasia of Cervical Spinous Process Presenting as Subcutaneous Mass
  • DOI:
    10.1007/s12098-013-1315-1
  • 发表时间:
    2013-12-22
  • 期刊:
  • 影响因子:
    2.000
  • 作者:
    Kanwaljeet Garg;Guru Dutta Satyarthee;Chinmaya Dash;Pankaj Kumar Singh;Poodipedi Sarat Chandra;Bhawani Shankar Sharma
  • 通讯作者:
    Bhawani Shankar Sharma
Long Segment Bony Spur in Split Cord Malformation Type 1
  • DOI:
    10.1007/s12098-016-2244-6
  • 发表时间:
    2016-10-22
  • 期刊:
  • 影响因子:
    2.000
  • 作者:
    Kanwaljeet Garg;Pankaj Kumar Singh;Shashank Sharad Kale;Bhawani Shankar Sharma
  • 通讯作者:
    Bhawani Shankar Sharma
Advancements in robot-assisted incremental sheet hydroforming: a comparative analysis of formability, mechanical properties, and surface finish for rhomboidal and conical frustums

Pankaj Kumar Singh的其他文献

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{{ truncateString('Pankaj Kumar Singh', 18)}}的其他基金

Metabolic regulation of FOLFIRINOX acquired resistance in pancreatic cancer
FOLFIRINOX 在胰腺癌中获得性耐药的代谢调节
  • 批准号:
    10518247
  • 财政年份:
    2022
  • 资助金额:
    $ 42.2万
  • 项目类别:
Pancreatic Cancer ARTNet Center
胰腺癌 ARTNet 中心
  • 批准号:
    10707504
  • 财政年份:
    2022
  • 资助金额:
    $ 42.2万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10518244
  • 财政年份:
    2022
  • 资助金额:
    $ 42.2万
  • 项目类别:
Cancer Metabolism Core
癌症代谢核心
  • 批准号:
    10707540
  • 财政年份:
    2022
  • 资助金额:
    $ 42.2万
  • 项目类别:
Pancreatic Cancer ARTNet Center
胰腺癌 ARTNet 中心
  • 批准号:
    10518243
  • 财政年份:
    2022
  • 资助金额:
    $ 42.2万
  • 项目类别:
Cancer Metabolism Core
癌症代谢核心
  • 批准号:
    10518246
  • 财政年份:
    2022
  • 资助金额:
    $ 42.2万
  • 项目类别:
Metabolic regulation of FOLFIRINOX acquired resistance in pancreatic cancer
FOLFIRINOX 在胰腺癌中获得性耐药的代谢调节
  • 批准号:
    10707541
  • 财政年份:
    2022
  • 资助金额:
    $ 42.2万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10707537
  • 财政年份:
    2022
  • 资助金额:
    $ 42.2万
  • 项目类别:
Mitochondrial calcium signaling in pancreatic cancer metastasis and progression
胰腺癌转移和进展中的线粒体钙信号传导
  • 批准号:
    10363987
  • 财政年份:
    2022
  • 资助金额:
    $ 42.2万
  • 项目类别:
Mitochondrial calcium signaling in pancreatic cancer metastasis and progression
胰腺癌转移和进展中的线粒体钙信号传导
  • 批准号:
    10565949
  • 财政年份:
    2022
  • 资助金额:
    $ 42.2万
  • 项目类别:

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