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The Allee Effect in Tumor Initiation

肿瘤发生中的 Allee 效应

基本信息

批准号：
10334470
负责人：
Amy Brock
金额：
$ 43.92万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-07 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10334470
关键词：
Aging Behavior Biological Breast Cancer cell line Carrying Capacities Cell Communication Cell Culture Techniques Cell Proliferation Cells Collection Communication Communities Complement Data Dissection Ecosystem Epigenetic Process Exercise Experimental Designs Formulation Foundations Gene Expression Profile Goals Graph Growth Growth Factor Heterogeneity Individual Indolent Joints Kinetics Lesion Ligands Link Malignant Neoplasms Mammalian Cell Maps Mathematics Measurement Measures Mediating Microscopic Modeling Monitor Nutrient Oligonucleotides Oxygen Paracrine Communication Population Population Density Population Growth Population Sizes Prostate Regulation Resolution Resources Role Signaling Molecule Statistical Data Interpretation Structure Systems Biology Thyroid Gland Tissues Tumor Biology Tumor Cell Line anticancer research autocrine base cancer cell cancer heterogeneity cancer stem cell cell dimension fitness in vivo mathematical model member neoplastic cell novel paracrine phenomenological models prevent real time monitoring receptor receptor expression resilience single cell analysis statistics theories tool transcriptome sequencing transcriptomics tumor tumor growth tumor heterogeneity tumor initiation

项目摘要

SUMMARY In ecosystem modeling, the Allee effect describes a correlation between population size (number of members) and mean fitness (proliferation rate) of individuals. Increased proliferation with increased population size implies cooperative interactions. A contrasting principle in ecosystems is population “carrying capacity” which describes a decrease in growth rates with increasing population size, due to competition for limited resources. While the concept of carrying capacity has been studied in tumors (which may become limited in nutrients or oxygen), the Allee effect has been almost entirely overlooked. Allee effects are significant in small populations and thus may be critical to understanding the earliest steps in tumor iniation. To investigate the fundamental contribution of the Allee effect on tumor ecosystems requires the novel experimental designs and integration of quantitative experimental measurements with mathematical modeling. The overall goal of this project is to dissect the contribution of population size and cell-cell communication in a few selected, well-suited tumor cell lines through quantitative single-cell resolution, real-time monitoring of cell populations. Mathematical models of growth kinetics will show that the Allee effect and cell-cell communication has consequences on a single cancer cell’s decision to initiate a growing tumor or to stay dormant. These communication networks will be further mapped by identification of specific paracrine factors and receptors. Disruption of the communication network that establishes a proliferative tumor will be performed by targeting specific cell subpopulation interactions. Perturbations will include depletion of specific cell subtypes, manipulation of overall paracrine signaling, and blocking of specific ligand-receptor combinations on interacting species. These strategies may be novel tools to trigger tumor cell population collapse. Population-level effects in a nascent tumor population have not been quantitatively explored and may explain the phenomenon of critical thresholds and define a mechanistic role for intratumor heterogeneity. This project focuses on a fundamental generic principle that is broadly applicable in many contexts and thus could complement and enrich the modeling efforts of the cancer research community.

总结在生态系统建模中，Allee效应描述了种群大小（成员数量）和个体的平均适合度（增殖率）。随着种群规模的增加，生态系统中的一个相对原则是人口的“承载能力”，描述了随着人口规模的增加，由于对有限资源的竞争，增长率下降。虽然已经在肿瘤中研究了承载能力的概念（其可能在营养物或代谢物中变得有限）， Allee效应在小种群中是显著的因此可能对理解肿瘤发生的最早阶段至关重要。 Allee效应对肿瘤生态系统的贡献需要新颖的实验设计和整合，定量实验测量与数学建模。该项目的总体目标是在少数几个选择性的、适合的肿瘤细胞中，分析群体大小和细胞间通讯的作用。通过定量单细胞分辨率、细胞群体的真实的实时监测来检测细胞系。数学模型生长动力学的研究表明，Allee效应和细胞-细胞通讯对单个细胞有影响，癌细胞的决定，启动一个不断增长的肿瘤或保持休眠。这些通信网络将通过识别特定的旁分泌因子和受体进一步映射。建立增殖性肿瘤的网络将通过靶向特定细胞亚群来进行干扰将包括特定细胞亚型的耗竭，对总体旁分泌的操纵，信号传导和阻断相互作用物种上的特异性配体-受体结合。这些策略可以是引发肿瘤细胞群体崩溃的新工具。新生肿瘤群体中的群体水平效应还没有被定量地探讨，并可能解释临界阈值的现象，并定义一个肿瘤内异质性的机制作用。这个项目的重点是一个基本的一般原则，广泛适用于许多情况，因此可以补充和丰富癌症的建模工作，研究社区。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Phenotypic Basis for Matrix Stiffness-Dependent Chemoresistance of Breast Cancer Cells to Doxorubicin.

DOI：
10.3389/fonc.2018.00337
发表时间：
2018
期刊：
Frontiers in oncology
影响因子：
4.7
作者：
Joyce MH;Lu C;James ER;Hegab R;Allen SC;Suggs LJ;Brock A
通讯作者：
Brock A

Integrating Quantitative Assays with Biologically Based Mathematical Modeling for Predictive Oncology.

DOI：
10.1016/j.isci.2020.101807
发表时间：
2020-12-18
期刊：
iScience
影响因子：
5.8
作者：
Kazerouni AS;Gadde M;Gardner A;Hormuth DA 2nd;Jarrett AM;Johnson KE;Lima EABF;Lorenzo G;Phillips C;Brock A;Yankeelov TE
通讯作者：
Yankeelov TE

Quantification of long-term doxorubicin response dynamics in breast cancer cell lines to direct treatment schedules.