The Bergers laboratory focuses on revealing the dialogue between the tumor cell compartment and the vascular niche, of which the vasculature is an integral component. The vascular niche consists of distinct cell types and specialized matrices that provide signals controlling stem cell proliferation, fate specification, and protection in not only normal tissue, but tumors, as well. The long-term goal of Dr. Bergers’ research is to conduct a comprehensive investigation that defines the heterotypical signals of the tumor-host dialogue in the vascular niche in regulating neovascularization, stem cell maintenance, and tumor invasion during tumor progression and therapeutic resistance.
Current Research Projects
Elucidate the dialogue of host and tumor stem cell constituents in the vascular niche
Glioblastoma mulitforme (GBM) is the most aggressive and prevalent brain tumor in adults, characterized by rapid and invasive growth, with patients having an overall median survival of only one year. A primary aim of Dr. Bergers’ research is to reveal the interaction of specific cell constituents in the vascular niche with the stem cell compartment in GBM during propagation and therapeutic manipulation of the niche. Specifically, her group intends to test the proposition that innate immune cells, recruited to the vascular niche by the tumor, can support tumor stem cell maintenance and propagation. Based on their previous data showing that intratumoral immune cell influx is enhanced with increased hypoxia, these cells may likely become pivotal players when the vascular niche is altered or destroyed, which they will test in vitro and in vivo using tumors from glioma-bearing mice treated with therapeutic agents that abrogate or prune the tumor vasculature.
The Bergers lab has shown that endothelial and immune cells of the tumor vascular niche are capable of providing signals that can promote an epithelial-mesenchymal (EMT)-like acquisition in GBM. The EMT-like acquisition elicits mesenchymal properties in tumor cells that maintain them in close proximity to blood vessels, which they use as tracks to invade into neighboring normal tissue. This effect becomes more prominent during antiangiogenic therapy, eliciting a proinvasive evasion mechanism, as observed in a subset of GBM patients. Indeed, the Bergers lab has found that vascular disruption due to antiangiogenic therapy can enhance signaling cues in the vascular niche that endorse EMT- and potentially stem cell-like traits in tumor cells. So far Dr. Bergers’ group has identified the interaction of the VEGF/VEGFR2 and HGF/cMet axis in eliciting this phenotype, as described below by the second research project. Expression profiling has revealed additional paracrine pathways that potentially drive an EMT-like program and “stem cellness” in GBM, a topic of future investigation.
Reveal heterotypical signaling circuits between the host and tumor compartment that incite evasive resistance to standard and targeted therapy
Leveraging from results obtained during the course of experimental therapy in their tumor models, it became apparent to the Bergers lab that relapsing tumor cells did not express cellular signals associated with resistance constitutively. Rather, they expressed these signals transiently, responding accordingly to contextual signals from their microenvironment during the course of treatment. Revealing the effects of antiangiogenic therapy in GBM has become particularly pivotal with the advent of bevacizumab, a humanized monoclonal antibody directed against VEGF. Bevacizumab has demonstrated therapeutic benefit in many GBM patients, showing improved progression-free survival and quality of life. However, the beneficial effects of bevacizumab are transient, and most GBM inevitably progress during anti-VEGF treatment. Dr. Bergers’ group has identified the molecular mechanisms by which VEGF ablation causes enhanced invasion, demonstrating that VEGF directly and negatively regulates tumor cell invasion through formation of a novel cMet:VEGFR2 receptor complex, which suppresses HGF-dependent c-Met phosphorylation and tumor cell migration. Consequently, VEGF blockade restores or increases c-Met activity in GBM cells in a hypoxia-independent manner while inducing an EMT-like program. These findings support combined treatment strategies targeting both VEGF and c-Met in GBM patients in order to overcome pro-invasive resistance and prolong survival.
Another major project implies the discovery of an oscillating population of distinct innate immune cells that conveys resistance by adapting quickly to antiangiogenic therapy, which Dr. Bergers’ group observed in mouse models of various tumor types, including pancreatic neuroendocrine tumors (PNET), GBM, and breast cancer. Although combined targeting of the vasculature and Gr1+CD11b+ monocytes has been shown to prolong response to anti-VEGF therapy, and the Bergers lab found an increase in Gr1+ monocytes in tumors evading anti-VEGF therapy, they observed that combinatorial treatment regimes blocking VEGF and Gr1+CD11b+ cells had very transient beneficial effects, followed by fast reneovascularization and regrowth. Ongoing studies reveal that distinct innate immune cell populations appear to compensate for each other when subsets are targeted, leading to an oscillating pattern to overcome growth restrictions. Recently, they have begun to investigate contextual signals from the tumor that regulate the nature, recruitment, and function of these distinct populations in these tumors.
Elicit the nature, regulation, and function of a novel resident stem cell-like population in PNET
The Bergers lab aims to characterize a novel population of multipotent cells with self-renewal capacity that resides in the niche of pancreatic islets and PNET. These cells exhibit both mesenchymal and pancreatic epithelial features, with the ability to differentiate into both mesenchymal cells (including endothelial cells and pericytes), as well as glucagon+ and insulin+ endocrine beta cells. The discovery of these multipotent mesenchymal stem cell-like cells (MPMSC) raises several questions as to the nature, regulation, and functional significance of MPMSC in PNET tumorigenesis. Given the highly vascular nature of pancreatic islets, MPMSC might be important for islet growth and injury, producing distinct cell types as necessary. Considering their ability to produce beta cells, these cells might also constitute a stem cell population for PNET tumors upon genetic aberration. Furthermore, MPMSC might become activated at the onset of angiogenesis and promote tumor propagation and progression by differentiating into endothelial cells and pericytes. Finally, MPMSC might produce proangiogenic factors and molecules that could potentially support invasion and/or metastasis formation, analogous to mesenchymal stem cells. Dr. Bergers’ group is testing these propositions by isolating these cells from human PNET samples, as well as by tracing MPMSC in mice in normal islets and through all stages of pancreatic tumorigenesis. MPMSC might offer not only new therapeutic targets for PNET, but also vast potential for tissue regeneration, specifically for pancreatic islet reconstitution in diabetic patients.