Cancer under pressure: Mechanisms of adaptation to compressive stress

压力下的癌症：适应压力的机制

基本信息

批准号：
10652254
负责人：
Liam J Holt
金额：
$ 45.67万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10652254
关键词：
Address Advanced Malignant Neoplasm Affect Automobile Driving Behavior Biological Process Biophysics Blood Vessels Cancer Biology Cancer Cell Growth Cell Survival Cell Volumes Cell physiology Cells Cellular biology Chemicals Clustered Regularly Interspaced Short Palindromic Repeats Crowding DNA Sequence Alteration Data Devices Drug Targeting Drug resistance Environment Evolution Gel Genes Genetic Growth Homeostasis Hypoxia Immunosuppression Individual Inflammation KRAS2 gene Lead Liquid substance Malignant Neoplasms Mechanics Microfluidic Microchips Microfluidics Molecular Mutation Normal Cell Oncogenes Oncogenic Organ Organism Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Phase Phenotype Physical environment Physiological Physiology Play Process Proliferating Property Qualifying Regulation Reproducibility Resistance Signal Transduction Solid Neoplasm Stress Survival Rate Technology Testing Tissues Viscosity barrier to care cancer cell cell behavior chemotherapy experimental study follow-up genome wide screen high throughput analysis innovation mechanical pressure mechanical properties migration mutant nanoparticle new technology new therapeutic target overexpression pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic tumorigenesis physical property physical state preference pressure prevent resistance gene response stress granule tool tumor tumor growth

项目摘要

Project summary Physical pressure is fundamentally important for cancer biology, but its effects remain poorly understood. When solid tumors grow confined within surrounding tissue, they build up compressive stress. Given that cells evolved to function in a stable mechanical environment, even slight changes in pressure perturb physiology. Normal cells and early stage cancer cells stop growing when pressure builds up. In contrast, in advanced cancer, compression can change cellular behavior to drive migration of cancer cells to other organs or confer resistance to chemo- therapy. This difference implies that cancer cells somehow adapt to physical pressure. A lack of tools has slowed progress in understanding the relationships between compression, the physical properties of cells, and cancer behavior. We developed two new technologies to overcome this limitation: First, we created a gene that enables cells to produce a steady supply of fluorescent nanoparticles that act as tell-tales for shifts in intracellular physical properties. Second, we developed microfluidic devices to control compressive stress, either quickly or slowly, while maintaining a constant chemical environment. We will combine these innovations to test the overarching hypothesis that mutations that confer resistance to mechanical compression enable pancreatic cancer cells to adapt to their high-pressure environment and drive their oncogenic evolution. Aim 1: We will determine how compression differentially impacts wildtype and mutant pancreatic cells. We will use GEM nanoparticles to quantify the physical response to pressure and test the hypothesis that oncogenic mutations alter both the physical and physiological response to pressure. Aim 2: We will determine the effects of compression on phase separation. We will investigate the hypothesis that decreased cell volume under pressure leads to in- creased phase separation of stress granules. We will evaluate molecular crowding as a mechanism for these effects. We will determine the importance of stress granule formation for mechanical adaptation and drug re- sistance. Aim 3: We will determine genetic mechanisms of pressure adaptation. We will follow up on pre- liminary mutants that confer resistance to compression, using a CRISPR modifier screen to determine mecha- nisms of adaptation. We will overexpress known oncogenes to find further adaptation pathways. Our innovative combination of genetic nanoparticles and microfluidic approaches, and our expertise that bridges biophysics, mechanobiology and cell biology make us uniquely qualified to connect compression, the physicochemical properties of cells, and cancer physiology. Our studies promise to reveal key network pertur- bations essential to cancer cell growth and survival under pressure. Understanding these adaptive mechanisms promises to suggest treatments that exploit the aberrant mechanical properties of tumors caused by high com- pressive stress.

项目摘要物理压力对于癌症生物学至关重要，但其影响仍然很少理解。什么时候实体瘤生长在周围组织中，会产生压缩应力。鉴于细胞进化为了在稳定的机械环境中发挥作用，即使是压力扰动生理的略有变化。正常细胞当压力累积时，早期癌细胞停止生长。相反，在晚期癌症中，压缩可以改变细胞行为以驱动癌细胞向其他器官迁移，或赋予对化学的抗性治疗。这种差异意味着癌细胞以某种方式适应了身体压力。缺乏工具已减慢了解压缩，细胞的物理特性与癌症之间的关系的进展行为。我们开发了两种新技术来克服这一局限性：首先，我们创建了一个基因细胞产生稳定的荧光纳米颗粒，这些纳米颗粒充当细胞内物理移动特性。其次，我们开发了微流体设备，以快速或缓慢地控制压缩应力，同时保持恒定的化学环境。我们将结合这些创新以测试总体假设赋予机械压缩性的突变使胰腺癌细胞能够适应其高压环境并推动其致癌性演变。目标1：我们将确定如何压缩会影响野生型和突变胰腺细胞。我们将使用宝石纳米颗粒为了量化对压力的物理反应并检验了致癌突变改变的假设对压力的身体和生理反应。目标2：我们将确定压缩的影响相分离。我们将研究以下假设：在压力下减少细胞体积会导致IN- 应力颗粒的相分离。我们将评估分子拥挤作为这些机制效果。我们将确定压力颗粒形成对机械适应和药物的重要性 Sistance。目标3：我们将确定压力适应的遗传机制。我们将跟进使用CRISPR修饰符屏幕确定机械的限制性突变体，以赋予压缩性。适应性。我们将过表达已知的癌基因，以找到进一步的适应途径。我们的遗传纳米颗粒和微流体方法的创新组合，以及我们的专业知识桥接生物物理学，机械生物学和细胞生物学使我们具有独特的条件来连接压缩，细胞的物理化学特性和癌症生理学。我们的研究有望揭示关键网络诉讼在压力下对癌细胞生长和存活必不可少的生物。了解这些适应性机制有望提出的治疗方法，以利用高肿瘤引起的肿瘤的异常机械特性压力压力。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chromosome clustering by Ki-67 excludes cytoplasm during nuclear assembly.

DOI：
10.1038/s41586-020-2672-3
发表时间：
2020-11
期刊：
Nature
影响因子：
64.8
作者：
Cuylen-Haering S;Petrovic M;Hernandez-Armendariz A;Schneider MWG;Samwer M;Blaukopf C;Holt LJ;Gerlich DW
通讯作者：
Gerlich DW

Condensed-phase signaling can expand kinase specificity and respond to macromolecular crowding.

DOI：
10.1016/j.molcel.2022.08.016
发表时间：
2022-10-06
期刊：
MOLECULAR CELL
影响因子：
16
作者：
Sang, Dajun;Shu, Tong;Pantoja, Christian F.;de Opakua, Alain Ibanez;Zweckstetter, Markus;Holt, Liam J.
通讯作者：
Holt, Liam J.

The environmental stress response regulates ribosome content in cell cycle-arrested S. cerevisiae.