Cancer under pressure: Mechanisms of adaptation to compressive stress

压力下的癌症：适应压力的机制

• 批准号: 10395568
• 负责人: Liam J Holt
• 金额: $ 46.6万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/10395568
• 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; Pharmaceutical Preparations; Phase; Phenotype; Physical environment; Physiological; Physiology; Play; Process; Property; Regulation; Reproducibility; Resistance; Signal Transduction; Solid Neoplasm; Stress; Survival Rate; Technology; Testing; Tissues; barrier to care; cancer cell; cell behavior; 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

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 物理压力对癌症生物学至关重要，但其影响仍然知之甚少。当 实体瘤生长局限于周围组织内，它们建立了压应力。考虑到细胞的进化 为了在稳定的机械环境中发挥作用，即使是轻微的压力变化也会扰乱生理学。正常细胞 早期癌细胞在压力增大时停止生长。相反，在晚期癌症中， 可以改变细胞行为，促使癌细胞迁移到其他器官，或赋予对化疗的抵抗力， 疗法这种差异意味着癌细胞以某种方式适应物理压力。由于缺乏工具， 在理解压缩、细胞物理特性和癌症之间的关系方面取得的进展 行为我们开发了两项新技术来克服这一限制：首先，我们创造了一种基因， 细胞产生稳定的荧光纳米颗粒供应，作为细胞内物理变化的信号。 特性.其次，我们开发了微流体装置来控制压缩应力，无论是快速还是缓慢， 同时保持恒定的化学环境。我们将联合收割机结合这些创新， 假设赋予对机械压迫抗性的突变使胰腺癌细胞能够 适应高压环境，推动致癌进化。目标1：我们将确定如何 压缩不同地影响野生型和突变胰腺细胞。我们将使用GEM纳米颗粒 为了量化对压力的身体反应，并测试致癌突变会改变 对压力的生理反应。目标2：我们将确定压缩对 相分离我们将研究在压力下细胞体积减少导致- 应力颗粒的折痕相分离。我们将评估分子拥挤作为这些机制 方面的影响.我们将确定压力颗粒形成对机械适应和药物再适应的重要性。 抵抗。目的3：我们将确定压力适应的遗传机制。我们将继续跟进前- 利用CRISPR修饰剂筛选，确定了赋予抗压缩性的潜在突变体， 适应的弊病。我们将过度表达已知的癌基因，以寻找进一步的适应途径。 我们的创新组合基因纳米粒子和微流体方法，以及我们的专业知识， 桥梁生物物理学，机械生物学和细胞生物学使我们唯一有资格连接压缩， 细胞的物理化学性质和癌症生理学。我们的研究有望揭示关键的网络干扰- 癌细胞在压力下生长和存活所必需的药物。了解这些适应机制 有望提出利用肿瘤的异常机械特性的治疗方法， 压力