Targeting MUC1-Mediated Tumor-Stromal Metabolic Cross-Talk in Pancreatic Cancer

靶向胰腺癌中 MUC1 介导的肿瘤-基质代谢交叉对话

• 批准号: 10738314
• 负责人: Pankaj Kumar Singh
• 金额: $ 5.48万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-25 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10738314
• 关键词: ATP Citrate (pro-S)-Lyase; Acetate-CoA Ligase; Acetates; Acetyl Coenzyme A; Acetylation; Biochemical; Biological Process; Cancer Etiology; Cell Survival; Cell secretion; Cells; Cessation of life; Clinical; Clinical Treatment; Clinical Trials; Cytoplasm; Desmoplastic; Development; Diagnosis; Enzymes; Epigenetic Process; Event; Extracellular Matrix; Family member; Gene Expression; Genes; Genetic; Genetic Engineering; Genetically Engineered Mouse; Glycolysis; Goals; Human; Invaded; Knock-out; Malignant neoplasm of pancreas; Mediating; Metabolic; Metabolism; Modeling; Molecular; Mucin 1 protein; Mus; Neoplasm Metastasis; Nutrient; Nutrient availability; Nutritional Support; Oncogenes; Oncogenic; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Phase III Clinical Trials; Primary Neoplasm; Production; Regulation; Role; Signal Transduction; Site; Stromal Cells; Stromal Neoplasm; Supporting Cell; Testing; Therapeutic; Transcriptional Activation; Translating; Transplantation; Tumor Burden; United States; cell growth; effective therapy; experimental study; hypercholesterolemia; hypoxia inducible factor 1; implantation; improved; inhibitor; innovation; insight; intraepithelial; knock-down; metabolomics; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; pancreatic cancer patients; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; pancreatic stellate cell; patient derived xenograft model; patient prognosis; pharmacologic; programs; promoter; response; stellate cell; three-dimensional modeling; transcriptional reprogramming; treatment response; tumor; tumor growth; tumor microenvironment; tumor progression

In the case of pancreatic cancer, early systemic dissemination, extraordinary local invasion, late diagnosis, and poor response to the existing chemotherapeutics contribute to an adverse patient prognosis. There is an urgent need to identify novel therapies that can significantly improve survival in patients. Tumor cells acquire as array of genetic, signaling, and epigenetic alterations that allow tumor cells to survive in harsh conditions and contribute to tumor progression, metastasis, and overall poor therapeutic response. Inhibiting the ability of tumor cells to survive in adverse conditions would diminish tumor progression and metastasis. Increasing evidence shows that tumor cells are reliant on certain nutrients in a manner dissimilar to non- transformed cells. We have identified that stabilization and activation of hypoxia-inducible factor-1 alpha by MUC1, an oncogene that confers aggressiveness in pancreatic cancer, contribute to the metabolic reprograming resulting in poor response to therapy. We have also observed that MUC1 regulates tumor cell metabolite exchange with stellate cells, a major constituent of desmoplasia in pancreatic tumors, thus facilitating tumor cell survival in low pH conditions. While abolishing the fibrotic stroma altogether could make tumors more invasive, novel therapeutic opportunities may be obtained by targeting specific features of the stellate cells that provide nutritional support for tumor cell survival in harsh conditions. Hence, we propose to investigate the efficacy of blocking the MUC1-mediated tumor-stromal metabolic crosstalk, which facilitates aggressiveness in pancreatic cancer. Such mechanisms regulate tumor cell growth and invasiveness in low pH conditions. Thus, these studies will promote the development of new and more effective treatment for metastatic pancreatic cancer. Our long-term goal is to determine the molecular basis of MUC1-mediated tumor-stromal metabolic cross- talk and how it facilitates invasiveness and metastasis in pancreatic cancer. In the first aim, we will investigate the impact of halting the utilization of stellate cell-secreted metabolites by tumor cells during pancreatic cancer progression and metastasis. In the second aim, we will elucidate the biochemical and molecular basis for MUC1- mediated activation of the transcriptional reprogramming that contributes to survival in low pH conditions, in response to stellate cell-secreted factors. In the third aim, we will investigate the potential of novel therapies that target the production of metabolites in stellate cells to support tumor cell survival in low pH conditions. Collectively, the proposed studies employ an innovative and integrative approach to determine the metabolic and signaling basis of MUC1-mediated tumor-stromal metabolic interactions that facilitate tumor progression and metastasis. Further, these studies will uncover novel therapeutic strategies to treat aggressive pancreatic cancer.

在胰腺癌的情况下，早期全身扩散，非凡的局部浸润， 晚期诊断和对现有化疗药物的不良反应导致患者预后不良。 迫切需要确定可以显着提高患者生存率的新疗法。肿瘤细胞 获得一系列遗传、信号传导和表观遗传改变，使肿瘤细胞在恶劣的环境中存活。 在某些实施方案中，肿瘤是一种恶性肿瘤，并且导致肿瘤进展、转移和总体治疗反应差。抑制 肿瘤细胞在不利条件下存活的能力将减少肿瘤进展和转移。 越来越多的证据表明，肿瘤细胞依赖于某些营养物质的方式与非营养物质不同。 转化细胞我们已经确定，缺氧诱导因子-1 α的稳定和激活， MUC 1是一种赋予胰腺癌侵袭性的癌基因，有助于代谢重编程 导致治疗反应不佳。我们还观察到MUC 1调节肿瘤细胞代谢产物 与星状细胞交换，这是胰腺肿瘤中结缔组织增生的主要成分，因此促进肿瘤细胞 在低pH条件下生存。虽然完全消除纤维化基质可能会使肿瘤更具侵袭性， 通过靶向星状细胞的特定特征， 营养支持肿瘤细胞在恶劣条件下的生存。因此，我们建议研究 阻断MUC 1介导的肿瘤间质代谢串扰，这有助于胰腺癌的侵袭性， 癌这些机制调节肿瘤细胞在低pH条件下的生长和侵袭性。这些研究 将促进新的和更有效的治疗转移性胰腺癌的发展。 我们的长期目标是确定MUC 1介导的肿瘤间质代谢交叉的分子基础， 以及它如何促进胰腺癌的侵袭和转移。在第一个目标中，我们将调查 胰腺癌期间肿瘤细胞停止利用星状细胞分泌的代谢产物的影响 进展和转移。在第二个目标中，我们将阐明MUC 1的生物化学和分子基础。 介导的转录重编程激活，有助于在低pH条件下存活， 对星状细胞分泌因子的反应。在第三个目标中，我们将研究新疗法的潜力， 靶向星状细胞中代谢产物的产生，以支持肿瘤细胞在低pH条件下的存活。 总的来说，拟议的研究采用了一种创新和综合的方法来确定代谢 和MUC 1介导的促进肿瘤进展的肿瘤-基质代谢相互作用的信号基础， 转移此外，这些研究将揭示治疗侵袭性胰腺癌的新治疗策略。

项目成果

ENT1 blockade by CNX-774 overcomes resistance to DHODH inhibition in pancreatic cancer.

• DOI: 10.1016/j.canlet.2022.215981
• 发表时间: 2023-01-01
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Mullen, Nicholas J.;Thakur, Ravi;Shukla, Surendra K.;Chaika, Nina, V;Kollala, Sai Sundeep;Wang, Dezhen;He, Chunbo;Fujii, Yuki;Sharma, Shikhar;Mulder, Scott E.;Sykes, David B.;Singh, Pankaj K.
• 通讯作者: Singh, Pankaj K.

Structure and function of human DnaJ homologue subfamily a member 1 (DNAJA1) and its relationship to pancreatic cancer.

人DNAJ同源物亚家族的结构和功能A成员1（DNAJA1）及其与胰腺癌的关系。

• DOI: 10.1021/bi401329a
• 发表时间: 2014-03-04
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Stark, Jaime L.;Mehla, Kamiya;Chaika, Nina;Acton, Thomas B.;Xiao, Rong;Singh, Pankaj K.;Monteione, Gaetano T.;Powers, Robert
• 通讯作者: Powers, Robert

MUC1 facilitates metabolomic reprogramming in triple-negative breast cancer.

• DOI: 10.1371/journal.pone.0176820
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Goode G;Gunda V;Chaika NV;Purohit V;Yu F;Singh PK
• 通讯作者: Singh PK

Combining DI-ESI-MS and NMR datasets for metabolic profiling.

结合DI-ESI-MS和NMR数据集用于代谢分析。

• DOI: 10.1007/s11306-014-0704-4
• 发表时间: 2015-04
• 期刊: METABOLOMICS
• 影响因子: 3.6
• 作者: Marshall, Darrell D.;Lei, Shulei;Worley, Bradley;Huang, Yuting;Garcia-Garcia, Aracely;Franco, Rodrigo;Dodds, Eric D.;Powers, Robert
• 通讯作者: Powers, Robert

Molecular Subtypes of Pancreatic Cancer: A Proteomics Approach.

胰腺癌的分子亚型：一种蛋白质组学方法。

• DOI: 10.1158/1078-0432.ccr-21-0640
• 发表时间: 2021-06-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Thakur R;Singh PK
• 通讯作者: Singh PK