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:10400713
- 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:3-DimensionalAddressAutomobile DrivingBackCancer EtiologyCancer PatientCell CountCell LineCellsCellular biologyCessation of lifeDataDiseaseDisseminated Malignant NeoplasmEpigenetic ProcessExtracellular MatrixFibronectinsFilopodiaGenesGenetic TranscriptionGenomicsHeterogeneityHistologicImageIndividualInvadedLungMalignant neoplasm of lungMechanicsMediatingMethylationModelingMolecularMolecular AnalysisMovementNeoplasm MetastasisPathway interactionsPatientsPhenotypePopulationPrevalencePublishingResearchResolutionResourcesShapesSignal TransductionSliceSolid NeoplasmStructure of parenchyma of lungSupporting CellTechniquesTestingTranscriptional ActivationWestern BlottingWidthXenograft Modelbasecancer cellcell population studycell typecohesionepigenomicsex vivo imagingfibrillogenesisgenome-widegenomic platformgenomic profilesimage guidedin vivoinsightlung cancer celllung tumorigenesismimicrymouse modelnotch proteinoverexpressionprogramspromoterspatiotemporaltherapeutic targettooltranscriptometumortumor 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.
项目总结
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:
10611926 - 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:
10159870 - 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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