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

描述（由申请人提供）：癌细胞独特的生物力学和生物物理特征代表了一种相对未开发的潜在生物标志物来源，可用于检测、诊断和监测癌症患者的治疗反应。这些不同的癌细胞表型可能将许多驱动癌症的分子异常整合为离散的、可量化的生物标志物，原则上，这些生物标志物可能比这种疾病中复杂的遗传景观更一致、更直接地进行评估。最近的研究表明，与正常或良性上皮细胞相比，来自多种悬浮组织的癌细胞系表现出对高水平流体剪切应力（FSS）短脉冲的抵抗力。这种表型反映了至少几种常见的致癌途径的信号传导。本提案的目的是确定对FSS的耐药性是否是具有临床诊断潜力的前列腺癌动物模型和人类黑色素瘤受试者组织的生物标志物。该建议的中心假设是，对流体剪切应力的抵抗是癌细胞的一种保守的生物物理特性，与疾病进展相关，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耐药与疾病的病理进展和/或对分子靶向治疗的反应有关，这些发现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长期反应，这是传统方法无法实现的。本提案的具体目的是：1)在动物模型中确定FSS耐药性是否与前列腺癌进展相关；2)确定对FSS的耐药性是否与人类黑色素瘤受试者组织中的药物敏感性有关。该提案的贡献将是显著的，因为它将验证FSS耐药是值得进一步研究和开发的临床相关生物标志物的概念。本方案采用一种简单的微流控分析方法，在两种不同的实验范式中测量FSS的耐药性，一种是基于动物的，另一种是在人体组织中。预计FSS升高与疾病进展相关，FSS降低与药物敏感性相关。拟议的研究具有创新性，因为它代表了一种快速而简单的方法来评估癌细胞群体对悬浮液中的机械力（FSS）的反应，这种悬浮液可以从临床标本中随时制备。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.