Relevance of circulating hybrid cells as a non-invasive biomarker for myriad solid tumors

Matthew S Dietz,Jerry J Jaboin,Charles D Lopez,Brett C Sheppard,Ajay Sapre,Rodney F Pommier,V Liana Tsikitis,Young Hwan Chang,Michael Parappilly,Sidharth K Sengupta,Gordon B Mills,Skye C Mayo,Thomas L Sutton,Charles E Gast,Joe W Gray,Alison H Skalet,Suellen J Pommier,Melissa H Wong,Brett S Walker,Jared M Fischer,Yu-Jui Chiu,Erik Burlingame ,Ariana Sattler,Luai Zarour,Kristen E Limbach ,John Swain ,Jennifer Eng,Yuki Chin,Jose L Mira ,Zahi Mitri,Austin Gower,Daniel Clayburgh ,Jeremy Cetnar ,Koei Chin

doi:10.1038/s41598-021-93053-7

Abstract

Metastatic progression defines the final stages of tumor evolution and underlies the majority of cancer-related deaths. The heterogeneity in disseminated tumor cell populations capable of seeding and growing in distant organ sites contributes to the development of treatment resistant disease. We recently reported the identification of a novel tumor-derived cell population, circulating hybrid cells (CHCs), harboring attributes from both macrophages and neoplastic cells, including functional characteristics important to metastatic spread. These disseminated hybrids outnumber conventionally defined circulating tumor cells (CTCs) in cancer patients. It is unknown if CHCs represent a generalized cancer mechanism for cell dissemination, or if this population is relevant to the metastatic cascade. Herein, we detect CHCs in the peripheral blood of patients with cancer in myriad disease sites encompassing epithelial and non-epithelial malignancies. Further, we demonstrate that in vivo-derived hybrid cells harbor tumor-initiating capacity in murine cancer models and that CHCs from human breast cancer patients express stem cell antigens, features consistent with the potential to seed and grow at metastatic sites. Finally, we reveal heterogeneity of CHC phenotypes reflect key tumor features, including oncogenic mutations and functional protein expression. Importantly, this novel population of disseminated neoplastic cells opens a new area in cancer biology and renewed opportunity for battling metastatic disease.

Highlights

Metastatic progression defines the final stages of tumor evolution and underlies the majority of cancer-related deaths
To determine if hybrid formation and escape is generalizable across cancer types, we evaluated peripheral blood for circulating hybrid cells (CHCs) from patients with 14 different epithelial or non-epithelial malignancies, including ampullary adenocarcinoma, breast adenocarcinoma, ovarian carcinoma, cholangiocarcinoma, colon adenocarcinoma, esophageal cancer, high grade glioma, head and neck squamous cell carcinoma, pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumor, prostate adenocarcinoma, rectal adenocarcinoma and uveal melanoma (Table 1)
As our prior analysis revealed CHC burden correlates with pancreatic ductal adenocarcinoma (PDAC) stage and patient survival, studies with larger cohorts should be pursued across cancer types to determine how CHC quantification might translate to clinical practice

Summary

Introduction

Metastatic progression defines the final stages of tumor evolution and underlies the majority of cancer-related deaths. We recently reported the identification of a novel tumor-derived cell population, circulating hybrid cells (CHCs), harboring attributes from both macrophages and neoplastic cells, including functional characteristics important to metastatic spread. These disseminated hybrids outnumber conventionally defined circulating tumor cells (CTCs) in cancer patients. We reveal heterogeneity of CHC phenotypes reflect key tumor features, including oncogenic mutations and functional protein expression This novel population of disseminated neoplastic cells opens a new area in cancer biology and renewed opportunity for battling metastatic disease. As a newly defined population, the functional tumor-initiating capacity and expression of stem cell attributes of CHCs is unexplored

Methods

Results

Conclusion