EFRI-BSBA: Photonic Technique for Sensing and Understanding Subcellular Structures at Nanoscale

本项目是生物光子学、大分子生物物理学、生物学和医学的交叉学科。该项目的主要重点是开发一种光子学技术，用于在纳米尺度上感测细胞结构的复杂性，并用于了解早期癌变过程中细胞纳米结构的变化，其潜在影响是推进癌变初始阶段的基础知识，并首次实现对广泛的主要癌症的人群筛查。该项目涉及以下两个BSBA要素：i）“工程，医疗保健，医学和生物研究实践和应用的范式转变”和ii）“纳米级传感，用于检测，识别，表征和理解纳米级亚细胞结构和过程的新型光子技术”。申请人已经开发了一种新的光学技术，单细胞分波光谱（PWS），其量化纳米级细胞结构的统计特性。使用PWS，我们证明了细胞纳米结构紊乱的增加是致癌作用中最早的事件之一，它先于任何已知的微尺度改变。重要的是，增加的纳米级紊乱并不限于肿瘤细胞，而是在整个器官中弥漫可见，从而作为现场致癌作用的标志。这为阐明决定这些纳米级变化及其在癌症进展中的作用的机制提供了动力，这是该项目的主要目标。使用PWS，将解决以下三个关键问题：i）细胞纳米结构紊乱的增加是基本上所有类型的上皮癌中发生的普遍现象吗？（二）这些变化的根源是什么？iii）纳米级紊乱的生物学意义和在致癌中的可能作用是什么？换句话说，这种改变是其他遗传事件的“副作用”，还是致癌的必要步骤？虽然人们普遍认为早期癌症筛查会大大降低癌症死亡率，但目前还没有准确筛查最致命癌症的测试。这在很大程度上是因为目前最先进的技术需要通过介入程序，如结肠镜检查，内窥镜检查，支气管镜检查等直接检查已经形成的癌前病变。这些程序是昂贵的，费力的，侵入性的，患者耐受性不好，导致筛查率非常低。该项目可能导致一种新的癌症筛查的一般范例，其中通过对可能位于离肿瘤病灶一定距离的器官的容易接近的部分中的非肿瘤组织的非侵入性光学分析来检测肿瘤的存在。其设想是，这种方法可用于筛查主要类型的癌症，例如，在年度体检期间，例如通过分析直肠细胞确定结肠腺瘤患者，通过分析颊细胞确定肺癌患者，通过分析十二指肠细胞确定胰腺癌患者，通过分析子宫或宫颈细胞确定卵巢癌患者，通过分析食管上部鳞状粘膜确定食管腺癌患者。从教育的角度来看，该项目将为研究生、本科生和高中生提供在生物光子学、分子生物物理学和癌症生物学领域进行真正跨学科研究的机会，特别注重在科学领域招募妇女和少数民族。研究结果将纳入PI指导的两个研究生班。项目执行过程中产生的调查结果和数据将分发给科学界。还将向公众传播主要调查结果。

ABSTRACT Photonic technique for sensing and understanding subcellular structures at nanoscale PI: Vadim Backman This project is at the interface of biophotonics, macromolecular biophysics, biology and medicine. The main focus of the project is the development of a photonics technique for sensing the complexity of cellular structure at the nanoscale and its use for understanding alterations in cell nanoarchitecture in early carcinogenesis with the potential impact to advance fundamental knowledge of the initial stage of carcinogenesis and enable, for the first time, population-wide screening for a wide range of major cancers. The project addresses the following two BSBA elements: i) "paradigm shift in practices and applications in engineering, health care, medicine, and biological research" and ii) "sensing at the nanoscale, novel photonic techniques for detecting, identifying, characterizing, and understanding subcellular structures and processes at nanoscale". The applicants have developed a novel optical technique, single-cell partial-wave spectroscopy (PWS), which quantifies the statistical properties of nanoscale cellular structure. Using PWS, we demonstrated that an increase in the disorder of cell nanoarchitecture is one of the earliest events in carcinogenesis which precedes any known microscale alterations. Importantly, the increased nanoscale disorder is not restricted to tumor cells but seen diffusely throughout the organ thus serving as a marker of field carcinogenesis. This provides the impetus to elucidate the mechanisms that determine these nanoscale changes and their role in cancer progression, which is the main goal of this project. Using PWS the following three key questions will be adressed: i) Is the increase in the disorder of cell nanoarchitecture a general phenomenon that takes place in essentially all types of epithelial cancers? ii) What is the origin of these changes? iii) What are the biological implications and possible role in carcinogenesis of the nanoscale disorder? In other words, is this alteration a "side-effect" of other genetic events or is it a necessary step in carcinogenesis? Although it is well accepted that early cancer screening would dramatically decrease cancer mortality, no test currently exists for accurate screening of the most lethal cancers. This is largely because the current state-of-the-art requires direct examination of an already formed precancerous lesion through interventional procedures such as colonoscopy, endoscopy, bronchoscopy, etc. These procedures are expensive, laborious, invasive and not well tolerated by patients, leading to very poor screening rates. This project may lead to a new general paradigm of cancer screening where the presence of neoplasia is detected by the non-invasive optical analysis of non-neoplastic tissue that might be located at a distance from the neoplastic focus in an easily accessible part of the organ. The vision is that this methodology may enable screening for the major types of cancer, for example, during an annual physical exam. Examples include identifying patients with colonic adenomas by analysis of rectal cells, lung cancer by analysis of buccal cells, pancreatic cancer by analysis of duodenal cells, ovarian cancer through analysis of uterine or cervical cells and esophageal adenocarcinoma through analysis of upper-esophageal squamous mucosa. From the educational perspective, the project will provide opportunities in truly interdisciplinary research at the interface of biophotonics, molecular biophysics and cancer biology for graduate, undergraduate and high school students with a particular focus on recruitment of women and minorities in science. The findings will be incorporated into two graduate classes directed by the PI's. The findings and data generated during the course of the project will be disseminated to the scientific community. The main findings will also be disseminated to the general public.