Mechanisms of Neoplastic Hybrid Cell Dissemination in Colorectal Cancer

Project Summary
Metastatic disease is the primary cause of cancer morbidity and mortality, resulting in >10 million deaths
worldwide in 2020. Despite recent advances in our knowledge of metastatic tumor development, there is a critical
need to understand the molecular mechanisms by which discrete subpopulations of neoplastic cells successfully
enter circulation to improve strategies for monitoring and reducing metastatic disease burden. Our team
discovered a unique disseminated neoplastic cell subtype characterized by co-expression of neoplastic and
immune cell genotypes and phenotypes that can form from neoplastic-macrophage cell fusion. These hybrid
cells are found in peripheral blood at numbers greater than other circulating tumor-derived cells (CTCs) and
exhibit increased migratory and invasive potential as well as the ability to seed and expand at metastatic sites at
rates greater than CTCs. However, the mechanisms by which hybrid cells do so is currently unknown. In my
preliminary analyses of hybrid cell gene expression, I identified upregulated components from the Runt-related
transcription factor 1 (RUNX1) pathway in hybrid cells compared to tumor cells. RUNX1 is a transcription factor
that regulates hematopoietic stem cell differentiation and macrophage migration and has been shown to mediate
metastatic conversion of tumor cells by facilitating epithelial-to-mesenchymal transition in colorectal cancer. In a
hybrid cell, RUNX1 may integrate the functional behaviors of both macrophages and tumor cells into a single
cell and facilitate their successful dissemination. Therefore, I hypothesize that disseminated subpopulations of
neoplastic hybrid cells display differential RUNX1 meditated ~omics and functional expression that facilitates
enhanced tumor dissemination.
This project proposes to first assess the gene expression and phenotypic profiles of hybrid cells in colorectal
cancer tumors and peripheral blood to identify characteristics of hybrid cells that successfully disseminate.
Additionally, this project will evaluate the functional role of RUNX1 in facilitating enhanced hybrid cell migration
and dissemination. Successful completion of these studies will define the molecular underpinnings of neoplastic
hybrid cell migration and dissemination and will provide the basis for future exploration of this unique neoplastic
subtype as a biomarker for the detection of early metastatic disease and tumor evolution.
Furthermore, this application proposes a comprehensive and interdisciplinary training plan within a prominent
academic medical and research institution that seamlessly integrates with the research proposal, providing
essential training in systems and molecular cancer biology to support the candidates career goal of maintaining
an academic translational oncology laboratory as a physician scientist.

Grant Number: 5F31CA271676-04
NIH Institute/Center: NIH
Principal Investigator: Ashley Anderson