Determinants of Liver Metastasis
肝转移的决定因素
基本信息
- 批准号:10295701
- 负责人:
- 金额:$ 11.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAffectAftercareAgingAndrogensBiologicalBiological AgingCancer PatientCarcinomaCellsCoculture TechniquesDioxygenasesEngraftmentEnvironmentEpigenetic ProcessEpithelialEpithelial CellsFibroblastsGene ExpressionGenesGeneticGlutamatesGlutamineHepaticHigh Fat DietInterventionLigandsLipidsLiverMalignant NeoplasmsMalignant neoplasm of prostateMetastatic Neoplasm to the LiverMutateNeoplasm MetastasisPatientsPrimary NeoplasmProstateProstate Cancer therapyProstatic NeoplasmsRoleSignal TransductionTestingTissuesTumor Expansionadvanced prostate cancerbasecurative treatmentsexperienceinhibitor/antagonistliver injurymethylation biomarkermethylation patternneuroendocrine differentiationnon-alcoholic fatty liver diseasenovelpromoterprostate cancer cellprostate cancer metastasistumortumor growthtumor microenvironment
项目摘要
Project Summary/Abstract.
Non-alcoholic fatty liver disease can make the liver permissive to liver metastasis. Patients taking an androgen
signaling inhibitor, such as enzalutamide for the treatment of prostate cancer can experience similar biologic
changes to the liver. These systemic changes in the patient lipid profile are associated with liver injury can result
in a quantifiable acceleration of biologic aging of the liver tissue. Prostate cancer cells acquire genetic
adaptations that enable survival in the liver as a metastatic niche. We found that enzalutamide exposure
promoted expression of BMP ligands in prostate cancer epithelial cells in a glutamine signaling-dependent
manner. Enzalutamide also increased expression of SLC1A5, a glutamine transporter able to regulate tumor
growth. Prostate cancer epithelial cells grown without glutamine had significantly lower levels of BMP ligands
compared to cells treated with glutamine, glutamate or enzalutamide. Glutamine inhibition was found to block
expression of SLC1A5 in prostate epithelia co-cultured with prostate cancer-associated fibroblasts. The
mechanism of transporting glutamine into the epithelial cells was sufficiently blocked using these inhibitors, and
fibroblast-specific genes were also affected. Wnt3a expression and glutamine secretion in prostate cancer-
associated fibroblasts increased after enzalutamide but decreased with glutamine inhibition. Based on these
novel findings, we tested if glutamine inhibition could be effective on the prostate tumor microenvironment, where
prostate cancer epithelia and cancer-associated fibroblasts were co-cultured. We found that enzalutamide
increased neuroendocrine differentiation in prostate epithelia, abrogated when co-cultures were treated with
glutamine inhibitor alone or in combination with enzalutamide. The potential role of enzalutamide on methylation
markers associated with biologic aging was observed where prostate epithelia treated with enzalutamide had
increased promoter enrichment of TET2 on its downstream target TBX2; glutamine inhibition decreased
promoter enrichment. We hypothesize that biologic aging of the liver induced by high fat diet impacts the hepatic
microenvironment to permit prostate metastasis. In Aim 1, we will define epigenetic changes in the liver that
occur as a result of androgen signaling inhibition using enzalutamide. We will determine how high fat diet
influences methylation patterns in the liver in a tumor-free environment. In Aim 2, we will identify the role of
biologic aging in the liver induced by high fat diet or enzalutamide treatment after primary tumor expansion
occurs. We found that prostate cancer epithelial expression of TET2, a methylcytosine dioxygenase mutated in
cancers, is increased with enzalutamide or glutamine treatments. We will explore the androgen-TET2 crosstalk
in prostate cancer epithelia as an adaptation promoting liver metastasis. The mechanism by which high fat diet
and liver aging contribute to prostate cancer metastasis to the liver will be studied.
项目总结/抽象。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Neil A. Bhowmick其他文献
First-line Immune Checkpoint Inhibitor Combinations in Metastatic Renal Cell Carcinoma: Where Are We Going, Where Have We Been?
- DOI:
10.1007/s40265-022-01683-6 - 发表时间:
2022-02-17 - 期刊:
- 影响因子:14.400
- 作者:
Jacob J. Adashek;Joshua J. Breunig;Edwin Posadas;Neil A. Bhowmick;Leigh Ellis;Stephen J. Freedland;Hyung Kim;Robert Figlin;Jun Gong - 通讯作者:
Jun Gong
603: Prostate Androgen Responsiveness Involve Stromal Transforming Growth Factor-Beta Signaling
- DOI:
10.1016/s0022-5347(18)37865-0 - 发表时间:
2004-04-01 - 期刊:
- 影响因子:
- 作者:
Neil A. Bhowmick;Susan Kasper - 通讯作者:
Susan Kasper
413: The Conditional Knock-Out of Transforming Growth Factor-Beta Signaling in the Prostate Stroma Results in Prostate Intraepithelial Neoplasia
- DOI:
10.1016/s0022-5347(18)37675-4 - 发表时间:
2004-04-01 - 期刊:
- 影响因子:
- 作者:
Neil A. Bhowmick;Harold L. Moses - 通讯作者:
Harold L. Moses
CD105 blockade restores osimertinib sensitivity in drug-resistant EGFR-mutant non-small cell lung cancer
CD105阻断可恢复耐药的表皮生长因子受体(EGFR)突变型非小细胞肺癌对奥希替尼的敏感性
- DOI:
10.1016/j.drup.2025.101237 - 发表时间:
2025-07-01 - 期刊:
- 影响因子:21.700
- 作者:
Manish Thiruvalluvan;Sandrine Billet;Zhenqiu Liu;Joseph Lownik;Barliz Waissengrin;Hyoyoung Kim;Anton L. Villamejor;Larry Milshteyn;Xiamo Li;Matthew Gayhart;Manuel Araña;Kamya Sankar;Edwin M. Posadas;Jean Lopategui;Sungyong You;Karen L. Reckamp;Neil A. Bhowmick - 通讯作者:
Neil A. Bhowmick
171: Expression of Dominant Active Transforming Growth Factor-Beta Receptor in Fetal Rat Bladder Stromal Cells
- DOI:
10.1016/s0022-5347(18)37433-0 - 发表时间:
2004-04-01 - 期刊:
- 影响因子:
- 作者:
Jeffrey M. Donohoe;John C. Pope;Neil A. Bhowmick;Mark C. Adams;John W. Brock;Simon W. Hayward - 通讯作者:
Simon W. Hayward
Neil A. Bhowmick的其他文献
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{{ truncateString('Neil A. Bhowmick', 18)}}的其他基金
Project 1- Role of fat in metastatic engraftment and expansion in the liver
项目 1 - 脂肪在肝脏转移植入和扩张中的作用
- 批准号:
10807146 - 财政年份:2020
- 资助金额:
$ 11.75万 - 项目类别:
Project 1- Role of fat in metastatic engraftment and expansion in the liver
项目 1 - 脂肪在肝脏转移植入和扩张中的作用
- 批准号:
10558474 - 财政年份:2020
- 资助金额:
$ 11.75万 - 项目类别:
Project 1- Role of fat in metastatic engraftment and expansion in the liver
项目 1 - 脂肪在肝脏转移植入和扩张中的作用
- 批准号:
10331757 - 财政年份:2020
- 资助金额:
$ 11.75万 - 项目类别:
The paradoxical roles of beta hydroxy butyrate in the liver pro-metastatic niche
β-羟基丁酸在肝脏促转移生态位中的矛盾作用
- 批准号:
10745869 - 财政年份:2020
- 资助金额:
$ 11.75万 - 项目类别:
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