(PQC2)Nanoscale changes in 3D nuclear architecture during breast tumorigenesis

描述（由申请人提供）：该拟议项目是为了解决C组的挑衅性问题2：“如何利用肿瘤的物理特性，如细胞的电学，光学或机械特性，提供更早或更可靠的癌症检测，诊断，预后，或监测药物反应或肿瘤复发？“我们将研究在癌变过程中细胞核的光学特性及其相关的纳米级结构变化，并确定其在提供乳腺癌早期和更准确诊断和预后方面的准确性。我们假设，核结构的纳米级改变发生在癌变的早期，并且容易获得的核结构纳米级变化的光学标记物的测量可以作为早期和更准确的癌症诊断和预后的具有成本效益和准确的工具。我们的小组已经开发了一套光学显微镜系统，可以使用临床获得的常规福尔马林固定和石蜡包埋的组织，全面表征癌变过程中核结构的3D纳米级变化。我们的光学显微镜系统包括深度分辨空间域低相干定量相位显微镜（深度分辨SL-QPM）和空间频率光谱编码（SESF）。我们发现，深度分辨的SL-QPM检测结构变化的灵敏度为1 nm的单细胞核内，而SESF提取的结构长度尺度分布的精度约为10-20 nm。我们广泛的初步数据表明，这些光学标记物有望检测多种肿瘤类型的组织学正常细胞中浸润性癌症的存在，并预测癌症进展风险。现在，我们建议使用这两种光学显微镜系统与最先进的3D超分辨率显微镜一起，定义一组光学标记和核结构中的潜在纳米级变化，这些变化是肿瘤发生的每个阶段的特征，并识别那些检测“癌前”变化的标记。然后，我们将进行临床研究，以评估核结构中纳米级变化的光学标记物的准确性，以预测具有癌前病变的女性中的乳腺癌进展风险（例如，非典型增生（AH））和导管原位癌（DCIS）的浸润前癌，以避免过度治疗。该项目如果成功，将建立肿瘤发生过程中纳米核结构的改变，并对肿瘤生物学研究和临床护理产生深远影响。这将为未来使用核结构中纳米级变化的光学标记物作为准确的预后标记物来预测那些可能进展为浸润性癌症的妇女奠定坚实的基础。

DESCRIPTION (provided by applicant): This proposed project is to address provocative question 2 from Group C: "How can the physical properties of tumors, such as the cell's electrical, optical or mechanical properties, be used to provide earlier or more reliable cancer detection, diagnosis, prognosis, or monitoring of drug response or tumor recurrence?" We will investigate the optical properties and their associated nanoscale architectural changes in the cell nucleus during carcinogenesis and determine their accuracy in providing earlier and more accurate diagnosis and prognosis of breast cancer. We hypothesize that the nanoscale alterations in nuclear architecture occur early in carcinogenesis and the measurement of easily obtained optical markers of nanoscale changes in nuclear architecture can serve as a cost-effective and accurate tool for earlier and more accurate cancer diagnosis and prognosis. Our group has developed a set of optical microscopy systems that can comprehensively characterize 3D nanoscale alterations in nuclear architecture in carcinogenesis using clinically obtained routine formalin-fixed and paraffin-embedded tissue. Our optical microscopy systems include depth-resolved spatial-domain low-coherence quantitative phase microscopy (depth-resolved SL-QPM) and spectral-encoding of spatial frequency (SESF). We showed that depth-resolved SL-QPM detects structural changes at a sensitivity of 1 nm within a single cell nucleus, while SESF extracts the structural length-scale distribution at an accuracy of ~10-20 nm. Our extensive preliminary data have shown the promise of these optical markers to detect the presence of invasive cancer even from histologically normal cells from multiple tumor types and predict cancer progression risk. Now we propose to use these two optical microscopy systems together with state-of-the-art 3D super-resolution microscopy, to define a set of optical markers and the underlying nanoscale changes in nuclear architecture that are characteristic of each phase of tumorigenesis and identify those that detect "premalignant" changes. Then we will perform a clinical study to evaluate the accuracy of optical markers of nanoscale changes in nuclear architecture to predict breast cancer progression risk among women with pre-cancerous lesions (e.g., atypical hyperplasia (AH)) and pre-invasive cancer of ductal carcinoma in situ (DCIS) to avoid over- treatment. This project, if successful, will establish the alterations of nanoscale nuclear architecture in carcinogenesis, and have profound impact on both tumor biology research and clinical care. It will build a solid foundation for future use of optical markrs of nanoscale changes in nuclear architecture as accurate prognostic markers to predict those women that are likely to progress into invasive cancer.