Mechanisms associated with organotropic metastasis
与器官转移相关的机制
基本信息
- 批准号:10295926
- 负责人:
- 金额:$ 51.01万
- 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:2021-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffectBlood VesselsBone MarrowBreast CarcinomaBreast cancer metastasisCancer PatientCellsCuesDataDiseaseDistantEndothelial CellsEndotheliumEnvironmentExpression ProfilingExtracellular MatrixExtravasationFibroblastsFibrosisGene DeletionGenetically Engineered MouseGrowthGrowth FactorHeterogeneityHomingImmuneInflammationIntercellular JunctionsKidneyLeadLiverLungLymphaticMalignant NeoplasmsMediatingMediator of activation proteinMetastatic Neoplasm to the KidneyMetastatic Neoplasm to the LungMolecularMolecular ProfilingMolecular TargetMusNeoplasm MetastasisNonmetastaticOrganProductionProteinsProteomicsPulmonary FibrosisReporterRepressionRoleRouteSeedsSignal TransductionSoilSolid NeoplasmSourceTestingTherapeuticTissuesTropismVascular Endothelial CellVascular EndotheliumVascular Permeabilitiescancer cellcell typecellular targetingchemokinecytokinedesignexosomeexperimental studyextracellular vesiclesgain of functioninsightkidney fibrosislung colonizationmalignant breast neoplasmmouse modelneoplastic cellnew therapeutic targetnovelrecruitsingle cell analysissingle cell technologysingle-cell RNA sequencingtumorvascular bed
项目摘要
ABSTRACT
Most cancer patients with solid tumors die of metastatic disease and organotropic spread is an understudied aspect
of metastasis, for which new insights are urgently required. The prevailing ‘seed and soil’ concept posits that
permissive environment in a distant organ (soil) is necessary to support the survival and growth of lurking tumor
cells (seeds). Induction of permissive soil in a non-metastatic organ is proposed to re-route metastasis; however,
rigorous experimental evidence and mechanistic analyses are lacking. Fibrotic tissue alterations, including
inflammation, provide cues for metastasis, together with the signals from bone marrow-derived cells (BMDCs),
the tumor secretome, and circulating extracellular vesicles. Our preliminary data suggest organotropic metastasis
is not solely dependent on permissive matrix remodeling and BMDCs in the secondary organs, but is also
contingent on the disruption of vascular endothelial barrier function imposed by organ-specific vascular junction
proteins. Our findings lead to a central hypothesis that ‘vascular heterogeneity functionally contributes to
organotropism of metastasis’. We propose studies to unravel the mechanisms, by which distinct fibrotic niches
effect organ-specific changes in the vascular beds, leading to organotropic metastasis. Preliminary studies
identified angiopoetin-2 (Ang-2) as a putative mediator of lung metastasis. We aim to unravel the mechanisms of
Ang-2 dependent tropism to the lung but not the kidney or liver, which also generate high Ang-2 levels in the
fibrotic setting. Using single-cell RNAseq and CyTOF, we will determine the cellular and molecular targets of
Ang-2 in the pre-metastatic milieu. Preliminary studies show Ang-2 induces vascular leakage in the lung
vasculature without impacting kidney or liver vessels, thus directing metastasis to the lung. Exosomes released
by the fibrotic organs also increase vascular permeability and metastatic colonization in the lung, without affecting
kidney or liver vasculature. Single-cell RNAseq of fibrotic organs, as well as genetically engineered mice
(GEMs), will be used to unravel the rate limiting effect of tissue-specific disruption of Ang-2 in breast cancer
metastasis. Using novel GEMs generated in the lab, we will trace lineage-specific production of metastasis-
inducing exosomes and identify the determinants of organotropism via proteomic analysis. Our preliminary
studies show Ang-2 disrupts vascular barriers through repression of claudin-5 that is found exclusively in the lung
vasculature, in contrast with the kidney and liver vessels, which present with multiple, redundant endothelial
claudins. Integrating mouse models with endothelial-specific deletion of claudin-5 and claudin-5 reporter mice,
and with molecular profiling of organ-specific endothelial cells in loss- and gain-of-function experiments, we will
elucidate functions of specific claudins in organotropic metastasis. Molecular studies will be performed to identify
putative mechanism of Ang-2 mediated suppression of claudin-5 and test whether manipulation of vascular
permeability can re-route metastasis regardless of cancer-specific organ predilection. Successful completion of
the proposed studies will provide new insights into mechanism of metastasis and therapeutic implications.
摘要
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
RAGHU KALLURI其他文献
RAGHU KALLURI的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('RAGHU KALLURI', 18)}}的其他基金
Mechanisms associated with organotropic metastasis
与器官转移相关的机制
- 批准号:
10439900 - 财政年份:2021
- 资助金额:
$ 51.01万 - 项目类别:
Mechanisms associated with organotropic metastasis
与器官转移相关的机制
- 批准号:
10532826 - 财政年份:2021
- 资助金额:
$ 51.01万 - 项目类别:
Employing mouse models to translate early detection of pancreas cancer
利用小鼠模型转化胰腺癌的早期检测
- 批准号:
8904197 - 财政年份:2015
- 资助金额:
$ 51.01万 - 项目类别:
Employing mouse models to translate early detection of pancreas cancer
利用小鼠模型转化胰腺癌的早期检测
- 批准号:
9097660 - 财政年份:2015
- 资助金额:
$ 51.01万 - 项目类别:
相似海外基金
A methodology to connect functionalized gonadal constructs to a chick embryo through mechanically induced blood vessels from an egg
一种通过鸡蛋机械诱导血管将功能化性腺结构连接到鸡胚胎的方法
- 批准号:
24K15741 - 财政年份:2024
- 资助金额:
$ 51.01万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
All-in-One Smart Artificial Blood Vessels
一体化智能人造血管
- 批准号:
EP/X027171/2 - 财政年份:2024
- 资助金额:
$ 51.01万 - 项目类别:
Fellowship
Development of nextgeneration cellular artificial blood vessels for coronary artery bypass surgery using bio-3D printer
使用生物 3D 打印机开发用于冠状动脉搭桥手术的下一代细胞人造血管
- 批准号:
23H02991 - 财政年份:2023
- 资助金额:
$ 51.01万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
ealization of navigation surgery by automatic recognition of stomach and surrounding blood vessels using artificial intelligence
利用人工智能自动识别胃及周围血管,实现导航手术
- 批准号:
23K07176 - 财政年份:2023
- 资助金额:
$ 51.01万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Realtime observation and optical control of living microbial probes in blood vessels
血管内活微生物探针的实时观察和光学控制
- 批准号:
23H00551 - 财政年份:2023
- 资助金额:
$ 51.01万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
Creation of a technique for visualization of stress concentration in blood and blood vessels by combined measurement of photoelasticity and ultrasonic Doppler velocimetry
通过光弹性和超声多普勒测速的组合测量,创建了一种可视化血管中应力集中的技术
- 批准号:
23H01343 - 财政年份:2023
- 资助金额:
$ 51.01万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Shear stress-activated synthetic cells for targeted drug release in stenotic blood vessels
剪切应力激活合成细胞用于狭窄血管中的靶向药物释放
- 批准号:
10749217 - 财政年份:2023
- 资助金额:
$ 51.01万 - 项目类别:
Creation of 3D tissue culture system integrated with blood vessels and autonomic nerves
打造血管与植物神经融合的3D组织培养系统
- 批准号:
23H01827 - 财政年份:2023
- 资助金额:
$ 51.01万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Biological function of osteoporotic drugs on bone-specific blood vessels and perivascular cells
骨质疏松药物对骨特异性血管和血管周围细胞的生物学功能
- 批准号:
22K21006 - 财政年份:2022
- 资助金额:
$ 51.01万 - 项目类别:
Grant-in-Aid for Research Activity Start-up