(PQC2) Resistance to fluid shear stress: a novel biomarker of cancer cells

描述（由申请人提供）：癌细胞的独特生物力学和生物物理特征代表了用于检测、诊断和监测癌症患者治疗反应的生物标志物的相对未开发的潜在来源。这些不同的癌细胞表型可以将许多驱动癌症的分子异常整合到离散的、可量化的生物标志物中，原则上，这些生物标志物可以比这种疾病中复杂的遗传景观更一致和更直接地进行评估。最近已经表明，与正常或良性上皮细胞相比，来自悬浮液中的许多组织的癌细胞系表现出对高水平流体剪切应力（FSS）的短暂脉冲的抗性。这种表型反映了通过至少几种常见致癌途径的信号传导。本提案的目的是确定对FSS的抗性是否是前列腺癌动物模型和人黑色素瘤受试者组织中具有临床诊断潜力的生物标志物。该提议的中心假设是，对流体剪切应力的抵抗是癌细胞的保守生物物理性质，其与疾病进展相关，并且可用于预测对治疗的反应。拟议研究的基本原理是，一旦确定FSS耐药性与疾病的病理进展和/或对分子靶向治疗的反应相关，这些发现就可以转化为一种新的临床诊断范式，用于预后评估或预测早期失败或传统方法无法实现的长期反应。本提案的具体目的是：1）确定动物模型中对FSS的耐药性是否与前列腺癌进展相关; 2）确定人黑色素瘤受试者组织中对FSS的耐药性是否与药物敏感性相关。这一提议的贡献将是显著的，因为它将测试FSS抗性是值得进一步研究和开发的临床相关生物标志物的概念。该提议采用简单的微流体测定来测量两个单独的实验范例中的FSS抗性，一个基于动物，一个在人体组织中。预计FSS增加与疾病进展相关，而FSS降低对应于药物敏感性。这项研究是创新的，因为它代表了一种快速简单的方法来评估癌细胞群体对悬浮液中机械力（FSS）的反应，悬浮液可以很容易地从临床标本中制备。这项工作的变革潜力在于，它可能为分子诊断提供另一种范式。

DESCRIPTION (provided by applicant): Unique biomechanical and biophysical features of cancer cells represent a relatively untapped potential source of biomarkers for the detection, diagnosis and monitoring of therapeutic response in cancer patients. These distinct cancer cell phenotypes may integrate a number of the molecular abnormalities driving cancer into discrete, quantifiable biomarkers that could, in principle, be more consistent and straightforward to assess than the complex genetic landscape in this disease. It has recently been shown that cancer cell lines from numerous tissues in suspension exhibit resistance to brief pulses of high level fluid shear stress (FSS) compared to normal or benign epithelial cells. This phenotype reflects signaling through at least several common oncogenic pathways. The objective of this proposal is to determine if resistance to FSS is a biomarker with clinical diagnostic potential in animal models of prostate cancer and tissue from human melanoma subjects. The central hypothesis of this proposal is that resistance to fluid shear stress is a conserved biophysical property of cancer cells that is associated with disease progression and can be used to predict response to therapy. The rationale for the proposed research is that once it is determined that FSS resistance is associated with pathologic progression of disease, and/or response to molecularly targeted therapies these findings can be translated into a novel clinical diagnostic paradigm for prognostic assessments or predicting early failure or prolonged response not possible with conventional approaches. The specific aims of this proposal are: 1) Determine if resistance to FSS is associated with prostate cancer progression in animal models; and 2) Determine if resistance to FSS is associated with drug sensitivity in tissue from human melanoma subjects. The contribution of this proposal will be significant because it will test the concept that FSS resistance is a clinically relevant biomarker worthy of further study and development. This proposal employs a simple microfluidic assay to measure FSS resistance in two separate experimental paradigms, one animal-based, one in human tissue. It is anticipated that increased FSS is associated with disease progression and decreased FSS corresponds to drug sensitivity. The proposed research is innovative because it represents a rapid and simple means to assess the response of a population of cancer cells to mechanical force (FSS) in suspensions that can be readily prepared from clinical specimens. The transformative potential of this work is that it may provide an alternative paradigm to molecular diagnostics.