In a groundbreaking study published in Science Translational Medicine, researchers at Weill Cornell Medicine and NewYork-Presbyterian have shed new light on a rare and enigmatic population of circulating tumor cells (CTCs) known as dual-positive (DP) cells. These hybrid cells, which co-express both epithelial and immune-cell markers, have been linked to significantly shorter survival times in patients with advanced breast cancer, particularly those with the aggressive triple-negative subtype. This discovery opens new avenues for understanding breast cancer progression and highlights the critical need to develop targeted therapies against these elusive cells.
Circulating tumor cells have long been recognized as critical players in cancer metastasis, acting as breakaway cancer cells that travel through the bloodstream and establish secondary tumors. Traditional CTC detection focuses on epithelial markers; however, dual-positive cells defy this norm by displaying both tumor epithelial markers such as cytokeratin and immune markers including CD45. This unique marker profile suggests that DP cells may arise through cell fusion events involving tumor cells and immune cells, particularly macrophages, resulting in hybrid cells that combine the phenotypic traits of both types.
The significance of DP cells has been hinted at in prior research involving melanoma and pancreatic cancer, where their presence correlated with worse clinical outcomes. Building on this foundation, the Weill Cornell team performed an extensive analysis of blood samples from 340 women with advanced breast cancer. They found that nearly 45% harbored at least one DP cell, with those exhibiting three or more DP cells facing a median survival of just 23.5 months. This stark statistic contrasts with 33.6 months for those with fewer than three DP cells, underscoring the dire prognostic implications associated with these hybrid cells.
The study’s granular examination revealed that the adverse impact of DP cells was predominantly observed in triple-negative breast cancer (TNBC) patients. TNBC is characterized by the absence of estrogen, progesterone, and HER2 receptors, rendering it notoriously difficult to treat. Unlike other breast cancer subtypes, TNBC is highly aggressive with limited targeted treatment options, making the association with DP cells particularly concerning. These findings suggest that DP cells contribute to the aggressive biology and poor outcomes associated with this subtype.
Further molecular investigations confirmed that approximately 60% of DP cells express macrophage-specific markers, supporting the hypothesis that they arise from rare fusion events between tumor cells and macrophages. In murine breast cancer models, DP cells were detectable only in animals with intact immune systems, providing additional evidence that the immune environment plays a crucial role in the generation of these hybrid cells. This insight points toward a complex interplay between tumor cells and immune cells that facilitates the emergence of DP cells in the tumor microenvironment.
DNA-level analyses added another layer of complexity, revealing that nearly 29% of patient-derived DP cells harbored copy number alterations—genetic abnormalities commonly seen in cancer cells. While this genetic instability was more frequently observed among conventional circulating tumor cells, the presence of such alterations in DP cells supports their tumorigenic potential. Notably, in vivo experiments demonstrated that these hybrid cells are fully capable of seeding metastases, highlighting their functional significance in cancer dissemination.
From a clinical perspective, the identification of DP cells as a distinct and dangerous circulating cell type challenges traditional paradigms that focus primarily on classical tumor cells. Current therapies designed to target typical epithelial tumor cells may fail to recognize the unique biology of these hybrids. According to Dr. Massimo Cristofanilli, senior author of the study, understanding the biology of DP cells is imperative for developing effective therapies that can target these cells and improve patient outcomes.
Ongoing investigations by the research team aim to provide a comprehensive molecular characterization of DP cells, including detailed gene expression profiling. This endeavor is expected to reveal crucial insights into the cellular origins and functional states of DP cells, potentially uncovering vulnerabilities that could be leveraged therapeutically. The ability to differentiate DP cells from conventional tumor cells at a molecular level could also enhance precision medicine approaches, enabling more accurate prognostication and treatment monitoring.
The implications of this research extend beyond breast cancer, as DP cells have been implicated in other malignancies such as melanoma and pancreatic cancer. The discovery of their role in breast cancer metastasis raises important questions about their broader role in oncology and metastasis biology. This line of inquiry represents a frontier in cancer research, marrying immunology with oncology to understand how cell fusion events may generate hybrid populations that drive disease progression.
Technological advances in liquid biopsy platforms have been instrumental in enabling the detection and analysis of these rare cell populations. The Weill Cornell team utilized state-of-the-art methods combining immunofluorescence and genetic analyses to identify and characterize DP cells in patient blood samples. These technological strides underscore the growing utility of liquid biopsies not only for diagnostics but also for uncovering novel cellular players that impact clinical outcomes.
As research on DP cells advances, it becomes increasingly clear that these hybrid tumor-immune cells represent a paradoxical entity. Their dual nature endows them with unique biological behaviors that likely contribute to their metastatic capacity and resistance to conventional therapies. Understanding the mechanisms behind their formation, survival, and dissemination will be crucial in devising next-generation therapeutics capable of combating the full spectrum of cancer cell heterogeneity.
In summary, the discovery of dual-positive circulating tumor cells as potent drivers of metastasis and poor prognosis in advanced breast cancer marks a pivotal moment in cancer biology. This novel cell population exemplifies the complex interrelationship between cancer and the immune system and challenges existing notions of tumor cell identity. As scientists continue to unravel the biology of DP cells, the hope is that these insights will translate into targeted interventions that improve survival and quality of life for patients facing this formidable disease.
Subject of Research: Advanced breast cancer; dual-positive circulating tumor cells
Article Title: Unusual Tumor Cells May Be Overlooked Factors in Advanced Breast Cancer
News Publication Date: 11-Mar-2026
Web References:
- Liquid Biopsy Platform at Englander Institute for Precision Medicine
- Englander Institute for Precision Medicine
- Sandra and Edward Meyer Cancer Center
Image Credits: Dr. Carolina Reduzzi
Keywords: Breast cancer, circulating tumor cells, dual-positive cells, metastasis, triple-negative breast cancer, tumor-immune cell fusion, copy number alterations, liquid biopsy, cancer biology
