Our lab works in basic and translational cancer research, tackling tumor heterogeneity from two different angles: a) Study of Cancer Stem Cells and b) Development, application and evaluation of Liquid Biopsy approaches in oncological patients.
Cancer stem cells
Cancer stem cells (CSCs) or tumor-initiating cells (TICs) constitute a small group of tumor cells that play an important role in the appearance and development of various types of cancer. CSCs have the abilities of self-renewal and differentiation and can support cancer progression, while the rest of the tumor cells have only limited proliferative capacity and do not significantly contribute to tumor growth.
According to the cancer stem cell model (Figure 1), the development of a tumor imitates that of normal tissue, following a specific differentiation pattern (from stem cells to transient amplifying cells to terminally differentiated ones), a process likely to be epigenetically regulated.
Several studies have shown that CSCs are more resistant to conventional cancer therapies, contributing to tumor metastasis and patient relapse after treatment (Figure 2).
To develop effective therapeutic schemes that target CSCs and lead to complete tumor eradication, we need to understand, first, their unique properties that allow them their self-renewal and tumor initiation capacity. A growing body of evidence suggests that these properties are under epigenetic regulation. However, there is, surprisingly, little data about the epigenome of CSCs. Our studies aim at filling this gap by revealing critical epigenetic components of cancer stem cell identity that may, also, serve as druggable targets for the development of CSC-specific therapies.
Breast Cancer Stem Cells
Breast cancer remains the most frequently diagnosed and the most fatal cancer in the female population (data source: Globocan 2018), despite advances in diagnosis and treatment. The highly heterogeneous nature of the disease represents a major obstacle to successful therapy and results in a significant number of patients developing drug resistance and, eventually, suffering from tumor relapse. Breast cancer stem cells have been implicated in the etiology of tumor recurrence due to their particularly malignant properties, including increased tumor initiating capacity and resistance to conventional therapeutic schemes.
To study the unique biological programs operating in breast CSCs, we have developed a well-characterized in vitro culture system comprised of tumorspheres that were generated from several breast cancer cell lines, representing different molecular subtypes, as well as, derived from tumor samples from breast cancer patients (Figure 3).
These tumorspheres/mammospheres are highly enriched in CSCs.
We implement a variety of molecular and cell biology in vitro assays, as well as, in vivo approaches using mouse xenografts, to investigate the epigenetic mechanisms that regulate self-renewal, tumor initiation capacity and therapy resistance in these cells.
- Study of the role of histone demethylase LSD1 (KDM1A) in the regulation of cancer stemness.
- The role of kallikrein-related peptidases in cancer stemness.
- Generation of EMT-derived breast CSCs; investigation of the epigenetic mechanisms in play.
- Application and evaluation of novel 3D systems for the in vitro culture of CSCs.
Liquid Biopsies In Cancer Management
(In collaboration with the Oncology Department-University of Ioannina)
With the advance of personalized medicine, in the last decade, new cancer biomarkers that describe the tumor molecular characteristics have emerged. Genetic differences in cancer patients may account both for the overall outcome of the disease and for the way they will respond to certain chemotherapeutics. Hence, these molecular alterations (mutations) can be used as biomarkers that have prognostic and predictive value respectively.
Tissue biopsy has been the gold standard for tumor molecular profiling; however, it is subject to considerable restrictions. Sampling and analyzing a small amount of tissue from one site may be inefficient, as it fails to reveal the whole cellular heterogeneity that characterizes most tumors. The dynamic nature of tumors, which evolve and are subject to new molecular changes, requires close monitoring of patients, ideally through multiple biopsies, in order to tailor targeted therapy accordingly. Since biopsy is a painful, technically difficult and often risky procedure for the patient, multiple biopsies are rather impractical. Finally, a tissue biopsy only from the primary tumor may not provide information about the molecular characteristics of metastases, which are the primary objective of systemic anticancer therapies.
Recently, "liquid biopsies" have emerged as a rapidly growing and promising field in translational cancer research. They include non-invasive techniques, which can overcome the limitations of tissue biopsy. Liquid biopsies are based on the analysis of biological material isolated from blood that contains information on the molecular characteristics of the tumor. Such biological material is circulating tumor DNA (ctDNA), circulating tumor cells and tumor-derived exosomes (Figure 4).
Currently, their most important application is the non-invasive and serial identification of oncogenic mutations of all cancerous lesions in a patient’s blood sample, allowing for the proper administration of a personalized regimen and the ability to monitor treatment response and development of resistance in real-time.
In collaboration with the Oncology Department of the University of Ioannina (Prof. G. Pentheroudakis), we participate in clinical studies investigating the clinical utility of ctDNA in patients with advanced lung, colorectal or pancreatic cancer.
- Cobas 480 z (Roche) for plasma EGFR testing in patients with advanced Non-Small Cell Lung Cancer. A highly sensitive allele specific Real-Time PCR system.
- Oncobeam (Sysmex-Inostics) for plasma KRAS/NRAS testing in patients with advanced colorectal and pancreatic cancer. The gold standard in plasma mutation detection based on the BEAMING-digital PCR system.