Deconstructing the collective invasion pack to define Myo10 function
解构集体入侵包定义Myo10功能
基本信息
- 批准号:10611926
- 负责人:
- 金额:$ 34.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-06 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAutomobile DrivingBackCancer EtiologyCancer PatientCell CountCell LineCellsCellular biologyCessation of lifeCommunicationDataDiseaseDisseminated Malignant NeoplasmEpigenetic ProcessExtracellular MatrixFibronectinsFilopodiaGenesGenetic TranscriptionGenomicsHeterogeneityHistologicImageIndividualInvadedLungMalignant neoplasm of lungMechanicsMediatingMethylationModelingMolecularMolecular AnalysisMovementNeoplasm MetastasisPathway interactionsPatientsPatternPhenotypePopulationPrevalencePublishingResearchResolutionResourcesShapesSignal TransductionSliceSolid NeoplasmStreamStructure of parenchyma of lungSupporting CellTechniquesTestingTranscriptional ActivationWestern BlottingWidthXenograft Modelangiogenesiscancer cellcell population studycell typeepigenomicsex vivo imagingfibrillogenesisgenome-widegenomic platformgenomic profilesimage guidedin vivoinsightlung cancer celllung tumorigenesismimicrymouse modelnotch proteinoverexpressionprogramspromoterspatiotemporaltherapeutic targetthree dimensional cell culturetooltranscriptometumortumor progression
项目摘要
Project Summary
Collective invasion is a major mode of metastasis observed in patients across most solid tumor types. How the
collective invasion pack operates, communicates, and navigates as a single cohesive unit remains unclear. To
address this, we published on an image-guided genomics platform to isolate any living cell(s) within a collective
invasion pack, and expand the population for genomic and molecular analysis, a technique termed
Spatiotemporal Cellular & Genomic Analysis (SaGA). We used SaGA to dissect the molecular, epigenetic, and
genomic profiles of leader and follower cells invading as a hierarchical cohesive unit. To determine how
epigenetic reprogramming drives this phenotypic heterogeneity, we deconstructed the collective invasion pack
using SaGA, then integrated genome-wide promoter methylation and transcriptome data to define differentially
methylated regions within the leader and follower phenotypes. We observe global epigenomic re-wiring in leader
cells supporting an epigenetic basis for the phenotypic heterogeneity within the collective invasion pack. We then
identified Myo10 (myosinX) as a top differentially methylated and expressed gene, where the leader cell
promoter is hypomethylated, and leaders in several lung cancer lines overexpress Myo10. Myo10 is a canonical
modulator of filopodia elongation and we show it drives filopodia elongation, collective invasion, leader cell-driven
fibronectin micropatterning (fibrillogenesis), and is transcriptionally activated by Jag1/Notch. We will use this
information to test a mechanistic model with the overarching hypothesis that Myo10 activation via promoter
hypomethylation in leader cells drives filopodia-based micropatterning of fibronectin to create a leader cell-driven
collective invasion path. We propose that this leads to an invasive advantage for lung cancer cells resulting in
metastatic disease. In Aim 1 we test the model that Myo10 hypomethylation in leaders allows for Jag1/Notch1-
driven transcriptional activation, driving filopodia elongation, and fibronectin micropatterning. In Aim 2 we test
how this collective invasion pathway impacts metastasis using in vivo metastasis models and the first patient-
derived leader cells. Throughout, we leverage unique resources developed here including SaGA-derived cell
lines, ex vivo imaging, and patient-derived lung cancer leader cells. We speculate that these data will provide
mechanistic insight into collective invasion and translational value towards understanding lung cancer patient
leader cell biology.
项目摘要
集体侵袭是在大多数实体瘤类型的患者中观察到的主要转移模式。如何
集体入侵包作为一个单一的内聚单位运作,通信和导航仍然不清楚。到
为了解决这个问题,我们发表了一个图像引导的基因组学平台,以分离集体中的任何活细胞。
入侵包装,并扩大人口的基因组和分子分析,一种技术称为
时空细胞和基因组分析(佐贺)。我们使用佐贺来剖析分子,表观遗传,
作为一个层次的凝聚性单位入侵的领导者和追随者细胞的基因组图谱。以确定如何
表观遗传重编程驱动了这种表型异质性,我们解构了集体入侵包,
使用佐贺,然后整合全基因组启动子甲基化和转录组数据,
在领导者和追随者表型内的甲基化区域。我们观察到领导者的全球表观基因组重新布线
细胞支持表观遗传基础的表型异质性内的集体入侵包。然后我们
发现Myo 10(myosinX)是一个甲基化和表达差异最大的基因,
启动子是低甲基化的,并且几种肺癌细胞系中的前导基因过表达Myo 10。Myo 10是一个典型的
丝状伪足伸长的调节因子,我们发现它驱动丝状伪足伸长,集体入侵,领导细胞驱动
纤连蛋白微图案化(纤维形成),并由Jag 1/Notch转录激活。我们将使用这个
信息,以测试具有总体假设的机制模型,即Myo 10通过启动子激活
前导细胞中的低甲基化驱动纤连蛋白的基于丝状伪足的微图案化,
我们认为,这导致肺癌细胞的侵袭优势,
转移性疾病在Aim 1中,我们测试了领导序列中Myo 10低甲基化允许Jag 1/Notch 1的模型-
驱动转录激活、驱动丝状伪足伸长和纤连蛋白微图案化。在目标2中,我们测试
使用体内转移模型和第一个患者,这种集体侵袭途径如何影响转移-
衍生的前导细胞。在整个过程中,我们利用这里开发的独特资源,包括SaGA衍生的细胞
细胞系、离体成像和患者来源的肺癌前导细胞。我们推测这些数据将提供
集体侵袭机制及其对理解肺癌患者的转化价值
领导细胞生物学。
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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Adam I. Marcus其他文献
TGF-β1-mediated intercellular signaling fuels cooperative cellular invasion
转化生长因子-β1(TGF-β1)介导的细胞间信号传导促进了细胞的协同侵袭。
- DOI:
10.1016/j.celrep.2025.115315 - 发表时间:
2025-02-25 - 期刊:
- 影响因子:6.900
- 作者:
Tala O. Khatib;Brian A. Pedro;Sergei Bombin;Veronika Y. Matsuk;Isaac E. Robinson;Sarah F. Webster;Landon J. Marcus;Emily R. Summerbell;Gregory K. Tharp;Christina M. Knippler;Pritha Bagchi;Jeanne Kowalski-Muegge;H. Rich Johnston;Homa Ghalei;Paula M. Vertino;Janna K. Mouw;Adam I. Marcus - 通讯作者:
Adam I. Marcus
High PER1 expression is associated with STK11 mutation and clinical biomarkers of immunotherapy resistance in lung adenocarcinoma
- DOI:
10.1007/s00432-025-06269-9 - 发表时间:
2025-07-26 - 期刊:
- 影响因子:2.800
- 作者:
Rebecca E. Parker;Leon McSwain;Wei Zhou;Adam I. Marcus;Haian Fu;Suresh S. Ramalingam;Shirley Zhang;Melissa Gilbert-Ross - 通讯作者:
Melissa Gilbert-Ross
A two dimensional simulation of microtubule dynamics
微管动力学的二维模拟
- DOI:
10.1109/itab.2008.4570630 - 发表时间:
2008 - 期刊:
- 影响因子:0
- 作者:
K. Kong;Adam I. Marcus;P. Giannakakou;Christopher Alberti;May D. Wang - 通讯作者:
May D. Wang
The pro-oncogenic noncanonical activity of a RAS•GTP:RanGAP1 complex facilitates nuclear protein export
RAS•GTP:RanGAP1 复合物的致癌非经典活性促进核蛋白输出
- DOI:
10.1038/s43018-024-00847-5 - 发表时间:
2024-11-11 - 期刊:
- 影响因子:28.500
- 作者:
Brajendra K. Tripathi;Nicole H. Hirsh;Xiaolan Qian;Marian E. Durkin;Dunrui Wang;Alex G. Papageorge;Ross Lake;Yvonne A. Evrard;Adam I. Marcus;Suresh S. Ramalingam;Mary Dasso;Karen H. Vousden;James H. Doroshow;Kylie J. Walters;Douglas R. Lowy - 通讯作者:
Douglas R. Lowy
Adam I. Marcus的其他文献
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{{ truncateString('Adam I. Marcus', 18)}}的其他基金
Project 3: Inhibiting FAK to enhance immune checkpoint inhibitor therapy in LKB1-mutant lung adenocarcinoma
项目3:抑制FAK增强免疫检查点抑制剂治疗LKB1突变型肺腺癌
- 批准号:
10411668 - 财政年份:2022
- 资助金额:
$ 34.97万 - 项目类别:
Project 3: Inhibiting FAK to enhance immune checkpoint inhibitor therapy in LKB1-mutant lung adenocarcinoma
项目3:抑制FAK增强免疫检查点抑制剂治疗LKB1突变型肺腺癌
- 批准号:
10631151 - 财政年份:2022
- 资助金额:
$ 34.97万 - 项目类别:
Implications of metabolic heterogeneity on collective lung cancer cell invasion
代谢异质性对肺癌细胞集体侵袭的影响
- 批准号:
10383657 - 财政年份:2021
- 资助金额:
$ 34.97万 - 项目类别:
Spatiotemporal interrogation of metabolic cooperation between heterogenous lung cancer subpopulations in collective cell invasion
集体细胞侵袭中异质肺癌亚群之间代谢合作的时空询问
- 批准号:
10818222 - 财政年份:2021
- 资助金额:
$ 34.97万 - 项目类别:
Implications of metabolic heterogeneity on collective lung cancer cell invasion
代谢异质性对肺癌细胞集体侵袭的影响
- 批准号:
10672179 - 财政年份:2021
- 资助金额:
$ 34.97万 - 项目类别:
Deconstructing the collective invasion pack to define Myo10 function
解构集体入侵包定义Myo10功能
- 批准号:
10159870 - 财政年份:2020
- 资助金额:
$ 34.97万 - 项目类别:
Deconstructing the collective invasion pack to define Myo10 function
解构集体入侵包定义Myo10功能
- 批准号:
10400713 - 财政年份:2020
- 资助金额:
$ 34.97万 - 项目类别:
Atypical Angiogenic Mimicry During Collective Lung Cancer Invasion
肺癌集体侵袭过程中的非典型血管生成拟态
- 批准号:
10439630 - 财政年份:2019
- 资助金额:
$ 34.97万 - 项目类别:
Atypical Angiogenic Mimicry During Collective Lung Cancer Invasion
肺癌集体侵袭过程中的非典型血管生成拟态
- 批准号:
9973155 - 财政年份:2019
- 资助金额:
$ 34.97万 - 项目类别:
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