Integrated Signaling in Pancreatic Cancer Progression

胰腺癌进展中的整合信号转导

• 批准号: 10247023
• 负责人: ROBERT S BRESALIER
• 金额: $ 36.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247023
• 关键词: Ablation; Attenuated; Automobile Driving; Cancer Biology; Cancer Center; Collection; Complement; Consequentialism; Data; Development; Disease; Down-Regulation; Epigenetic Process; Evaluation; Event; FOXM1 gene; Gene Expression; Genetic; Goals; Homeostasis; Human; In Vitro; Incidence; KPC model; KRASG12D; Lesion; Link; Malignant neoplasm of pancreas; Mediating; Modality; Modeling; Molecular; Molecular Target; Mus; Pancreas; Pancreatic Intraepithelial Neoplasia; Pathologic; Pathway interactions; Prevention strategy; Preventive; Proteins; Receptor Signaling; Regulation; Research; Resistance; Resources; Role; Signal Transduction; Specimen; Testing; Therapeutic; Therapeutic Effect; Tissues; Translations; Validation; Vitamin D; Vitamin D3 Receptor; clinically relevant; design; effective intervention; genetic manipulation; in vivo Model; malignant phenotype; mouse model; novel; overexpression; pancreatic cancer cells; pancreatic cancer patients; premalignant; public health relevance; receptor downregulation; receptor expression; receptor function; refractory cancer; response; restoration; transcription factor; treatment strategy; tumor progression

 DESCRIPTION (provided by applicant): Invasive pancreatic cancer (PDA) is a lethal disease. While certain genetic and epigenetic alterations have been well known for years, to date this has not resulted in useful preventive and/or therapeutic modalities. Our research goal is to identify driving alterations in gene expression that can be utilized to develop effective strategie to control PDA progression. Our previous studies have demonstrated that transcription factor FOXM1 is drastically increased in invasive PDA and this dysregulation critically promotes PDA biology, whereas PanINs do not exhibit substantially elevated FOXM1 expression. In sharp contrast, our recent study has shown a consistent lack of vitamin D receptor (VDR) expression in invasive PDA as compared to that in PanINs. Causally linking VDR loss to FOXM1 overexpression and functionally interrogating the underlying mechanisms are fundamentally important in understanding PDA progression. We postulate that downregulation of VDR expression causes FOXM1 overexpression and consequential acquisition of malignant phenotype in PDA, i.e., a switch from PanINs to invasive PDA. Therefore, activation and/or restoration of VDR signaling could attenuate PanINs progression and sensitize PDA to Vitamin D treatment. To test our hypothesis, we propose three specific aims: (1) Determine whether loss of VDR expression is a critical event of pancreatic cancer progression from PanIN to invasive PDA; (2) Determine the critical molecular mechanisms underlying dysregulation of VDR signaling in and its mechanistic impact on PDA progression; and (3) Determine whether an intact VDR signaling renders PanINs sensitive to Vitamin D treatment, while invasive PDA are refractory to Vitamin D due to loss of VDR expression. These three novel specific aims with clinical relevant question (aim 1), mechanistic substantiation (aim 2) and translational validation (aim 3), are supported by our respective preliminary data and can be tested independently using our unique research resources, yet they are highly interrelated and support one another. Our proposed studies will take advantage of the unique resources available at MD Anderson Cancer Center, including our large collection of pancreatic cancer specimens and mouse models. Given the important role of VDR/FOXM1 we have uncovered, we predict that completion of these studies will provide insightful information for the molecular basis of pancreatic cancer progression and for identification of molecular targets to design effective prevention and treatment strategies; and translation of our findings into benefiting PDA patients is our long term goal.

 描述（由申请人提供）：侵袭性胰腺癌（PDA）是一种致命疾病。虽然某些遗传和表观遗传改变多年来已为人们所熟知，但迄今为止，这尚未产生有用的预防和/或治疗方式。我们的研究目标是确定基因表达的驱动改变，可用于制定控制 PDA 进展的有效策略。我们之前的研究表明，转录因子 FOXM1 在侵袭性 PDA 中急剧增加，这种失调严重促进了 PDA 生物学，而 PanIN 并未表现出 FOXM1 表达显着升高。与此形成鲜明对比的是，我们最近的研究表明，与 PanIN 相比，侵入性 PDA 中始终缺乏维生素 D 受体 (VDR) 表达。将 VDR 丢失与 FOXM1 过度表达联系起来并从功能上探讨潜在机制对于理解 PDA 进展至关重要。我们假设 VDR 表达下调会导致 FOXM1 过度表达，从而导致 PDA 中恶性表型的获得，即从 PanIN 转变为侵袭性 PDA。因此，VDR 信号的激活和/或恢复可以减弱 PanINs 的进展并使 PDA 对维生素 D 治疗敏感。为了检验我们的假设，我们提出了三个具体目标：（1）确定 VDR 表达缺失是否是胰腺癌从 PanIN 进展为侵袭性 PDA 的关键事件； (2) 确定VDR信号失调的关键分子机制及其对PDA进展的机械影响； (3) 确定完整的 VDR 信号传导是否使 PanIN 对维生素 D 治疗敏感，而侵入性 PDA 由于 VDR 表达缺失而对维生素 D 无效。这三个新颖的具体目标包括临床相关问题（目标 1）、机制证实（目标 2）和转化验证 （目标 3），得到我们各自初步数据的支持，可以使用我们独特的研究资源进行独立测试，但它们高度相关并相互支持。我们提出的研究将利用 MD 安德森癌症中心的独特资源，包括我们收集的大量胰腺癌标本和小鼠模型。鉴于我们发现的 VDR/FOXM1 的重要作用，我们预测这些研究的完成将为胰腺癌进展的分子基础以及识别分子靶标以设计有效的预防和治疗策略提供富有洞察力的信息；将我们的发现转化为造福 PDA 患者是我们的长期目标 目标。

项目成果

Activation of Vitamin D/VDR Signaling Reverses Gemcitabine Resistance of Pancreatic Cancer Cells Through Inhibition of MUC1 Expression.

维生素 D/VDR 信号的激活通过抑制 MUC1 表达来逆转胰腺癌细胞对吉西他滨的耐药性。

• DOI: 10.1007/s10620-023-07931-3
• 发表时间: 2023
• 期刊: Digestive diseases and sciences
• 影响因子: 3.1
• 作者: Wei,Daoyan;Wang,Liang;Liu,Yi;Hafley,MargareteA;Tan,Lin;Lorenzi,PhilipL;Yang,Peiying;Zuo,Xiangsheng;Bresalier,RobertS
• 通讯作者: Bresalier,RobertS

Immune activation of the p75 neurotrophin receptor: implications in neuroinflammation.

• DOI: 10.3389/fnmol.2023.1305574
• 发表时间: 2023
• 期刊: FRONTIERS IN MOLECULAR NEUROSCIENCE
• 影响因子: 4.8
• 作者: Danelon, Victor;Garret-Thomson, Sarah C.;Almo, Steven C.;Lee, Francis S.;Hempstead, Barbara L.
• 通讯作者: Hempstead, Barbara L.

Vitamin D: Promises on the Horizon and Challenges Ahead for Fighting Pancreatic Cancer.

维生素D：承诺在地平线上，对抗胰腺癌的挑战。

• DOI: 10.3390/cancers13112716
• 发表时间: 2021-05-31
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Wei D;Wang L;Zuo X;Bresalier RS
• 通讯作者: Bresalier RS