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

描述(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记物来源，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会将导致癌症的一些分子异常整合成离散的、可量化的生物标记物，原则上，这些生物标记物可能比这种疾病的复杂遗传图景更一致和更直接地进行评估。最近有研究表明，与正常或良性上皮细胞相比，悬浮中的许多组织的癌细胞株对高水平流体切应力(FSS)的短暂脉冲具有抵抗力。这种表型至少通过几条常见的致癌途径反映了信号传递。这项建议的目的是确定在前列腺癌动物模型和人类黑色素瘤受试者组织中，对FSS的耐药性是否是一个具有临床诊断潜力的生物标记物。这一建议的中心假设是，对流体剪切力的抵抗是癌细胞的一种保守的生物物理特性，与疾病进展有关，可用于预测对治疗的反应。这项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延长反应，这是传统方法所不可能的。这项建议的具体目的是：1)在动物模型中确定对FSS的耐药性是否与前列腺癌的进展有关；以及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。这项建议的贡献将是重大的，因为它将检验FSS耐药是一个值得进一步研究和开发的临床相关生物标志物的概念。这项建议使用一种简单的微流控方法，在两个不同的实验范例中测量FSS的耐药性，一个基于动物，一个在人体组织中。预计FSS增加与疾病进展有关，而FSS减少对应于药物敏感性。这项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机械力(FSS)的反应，这种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，它可能为分子诊断学提供一种替代范式。

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.