Nanoscale Spectroscopy for Early Cancer Detection and Phenotypic Analysis

About This Grant

PROJECT SUMMARY Colorectal cancer (CRC) is the second leading cause of cancer deaths in the U.S. despite being preventable by colonoscopy through removal of premalignant lesions, such as advanced adenomas, the clinically significant precursor of CRC. While colonoscopy is recommended for all patients over the age of 45, many patients are not screened due to poor compliance, cost, and limited capacity to screen over 90 million eligible Americans. Attempting to perform colonoscopy on all average-risk patients is also inefficient: only 7% of patients have advanced adenomas. While current and emerging non-endoscopic CRC screening tests, including fecal and blood tests, might show sensitivity to cancers, they consistently fail to detect advanced adenomas. This failure is biologically fundamental and stems from the low yield of tumor biomarkers shed or secreted into the stool or blood by early lesions and tumor heterogeneity. We propose an alternate strategy that addresses these failures by integrating three key innovations. First, instead of sampling tumor secretions, we leverage the phenomenon of CRC field carcinogenesis: a histologically normal, preconditioned "field" that includes the entire colon and rectum and carries systemic transcriptional and epigenetic alterations predisposing the patient to neoplasia. This approach maintains high sensitivity regardless of lesion size. Second, we target chromatin-regulated transcriptional plasticity as a new class of biomarkers. We propose to integrate the measurements of alterations in nanoscopic, sub-Mbp chromatin packing domains—key elements of transcriptional memory that drive transcriptional plasticity necessary for pre-neoplastic cells to acquire malignant traits—and their transcriptomic consequences. This choice of biomarkers circumvents the problem with tumor heterogeneity. Third, we will develop chromatinomics: a new CRC screening platform integrating chromatin-sensitive optical spectroscopic nanosensing and global miRNA/mRNA transcriptomics, enhanced by highly multiplexed spectroscopic single molecule localization microscopy and mechanistically-guided AI analysis, and informed by chromatin-specific 3D electron tomography and predictive molecular modeling to detect transcriptional plasticity as a biomarker of CRC risk. This platform will be validated in a prospective, cross-sectional clinical study of a 500-patient average-risk cohort. Our long-term vision is to develop chromatinomics analysis of a simple, low-cost rectal swab, performed in primary care, as a high-accuracy, first-line prescreen to efficiently prioritize colonoscopy for patients harboring advanced adenomas. The ultimate goal is to significantly increase CRC screening uptake while reducing unnecessary procedures.