R01CA253860

Integrative Single Cell Analyses of Inflammation-Derived Circulating Hybrid Cells to Identify Aggressive Disease - Project Summary

The lifetime risk for acquiring colorectal cancer (CRC) is 7%, with an astounding rate of disease recurrence in 32% of newly diagnosed patients after their "successful" treatment. Patients with recurrent disease have a dismal 14.3% five-year survival. Lack of effective biomarkers hampers early detection of pre-metastatic disease, impacting overall survival from CRC.

We identified a promising disseminated tumor cell—a product of macrophage (M) and cancer cell fusion—that harbors genotypic and phenotypic features of both cells of origin. Detectable along the metastatic cascade, hybrid cells can initiate tumor growth, migrate in response to M receptor-ligand chemotaxis, and seed metastatic sites. In peripheral blood, hybrids, named circulating hybrid cells (CHCs), outnumber conventionally defined circulating tumor cells (CTCs) in CRC patients, overcoming the sensitivity of CTC—a primary barrier—to usage as a biomarker for disease. CHCs are phenotypically diverse and reflect protein expression of the primary tumor.

Based on these exciting findings, we propose that hybrid cell subpopulations harbor discrete phenotypes of pre-metastatic cells that can be identified and defined using single cell image-based phenotyping through multiplexed imaging and multimodal integration with -omics. To this end, we will analyze CHCs derived from early stage and metastatic tumors for image-based phenotyping with single cell gene expression. Utilizing quantitative and advanced image analytics including deep learning approach for image-based cell profiling, we will define inter/subcellular spatial features in single cells to identify new subpopulations and differentiate discrete phenotypic populations associated with metastatic signatures.

In addition, the application of both imaging and genomic technologies to the same specimen independently measures highly dimensional, yet non-orthogonal, sets of cellular features. Multimodal integration of imaging and single cell data will quantify systems-level biological functions of cellular subpopulations and enhance imaging biomarker panel to gain biomarker specificity and sensitivity for validation in a discrete CRC patient cohort.

Our overall goal is to develop a novel tumor biomarker, based upon CHC phenotyping and -omics analyses, that can be used to provide new quantitative insights and develop machine-driven prediction with superior accuracy for identifying risk of metastases in CRC patients to ultimately impact survival.

Oregon Health & Science University

TO IMPROVE SCREENING AND EARLY DETECTION STRATEGIES AND TO DEVELOP ACCURATE DIAGNOSTIC TECHNIQUES AND METHODS FOR PREDICTING THE COURSE OF DISEASE IN CANCER PATIENTS. SCREENING AND EARLY DETECTION RESEARCH INCLUDES DEVELOPMENT OF STRATEGIES TO DECREASE CANCER MORTALITY BY FINDING TUMORS EARLY WHEN THEY ARE MORE AMENABLE TO TREATMENT. DIAGNOSIS RESEARCH FOCUSES ON METHODS TO DETERMINE THE PRESENCE OF A SPECIFIC TYPE OF CANCER, TO PREDICT ITS COURSE AND RESPONSE TO THERAPY, BOTH A PARTICULAR THERAPY OR A CLASS OF AGENTS, AND TO MONITOR THE EFFECT OF THE THERAPY AND THE APPEARANCE OF DISEASE RECURRENCE. THESE METHODS INCLUDE DIAGNOSTIC IMAGING AND DIRECT ANALYSES OF SPECIMENS FROM TUMOR OR OTHER TISSUES. SUPPORT IS ALSO PROVIDED FOR ESTABLISHING AND MAINTAINING RESOURCES OF HUMAN TISSUE TO FACILITATE RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.394 - Cancer Detection and Diagnosis Research

National Cancer Institute (NCI) [HHS - NIH]

Portland, Oregon 972393011 United States

Single Zip Code

Imaging, Biomarkers and Digital Pathomics for the Early Detection of Premetastatic Aggressive Cancer (R01 Clinical Trial Optional) (PAR-19-264)

Amendment Since initial award the total obligations have increased 384% from $629,276 to $3,044,035.