The main research interest in my laboratory is to decipher the molecular and cellular mechanisms of tumor reprogramming. We seek to understand how tumor cells change their differentiation state, also referred to as tumor plasticity, and take advantage of this process to generate tumor heterogeneity and a constant pool of cancer stem cells/cancer propagating cells.
We also seek to understand the role of the tumor microenvironment in this process, to characterize the composition of the brain tumor microenvironment at the cellular and molecular level, and elucidate the cross-talk between tumor cells and non-transformed cells.
We believe that understanding these mechanisms and interactions will facilitate the development of novel strategies to attack this aggressive type of cancer.
Novel Therapeutic Approaches
Glioblastoma remains an incurable disease, for which standard-of-care treatments including surgery, radiotherapy and chemotherapy, are largely inadequate. Discovering new therapeutic strategies to attack glioblastoma is therefore an important goal.
Adoptive T cell transfer for cancer and chronic infection is an emerging field that shows promise in recent trials. Advances in cell engineering and culture approaches to enable efficient gene transfer and ex vivo cell expansion have facilitated broader evaluation of this technology, moving adoptive transfer from the bench to the cusp of a mainstream technology. The major challenge currently facing the field is to increase the specificity of engineered T cells for tumors, specifically in solid tumors, and to be able to elicit an effective long-lasting T-cell response.
Glioblastoma is both the most common and lethal primary malignant brain tumor. In the last century we have accumulated tremendous amounts of data on this type of cancer, but we have achieved very little improvement in its treatment. Previous work using our mouse GBM model and a nanosystem targeted to tumor vasculature that incorporates a proapototic peptide as a drug, showed that we can eradicate most tumors in one GBM model and delay the development of tumors in another more aggressive GBM model. Our goal now consists of a multidisciplinary approach: a novel cancer therapeutic modality that aims to exploit targeted nanoparticles and adoptive immunotherapy.
Gliomas, as their name state for, were thought to arise from glia (astrocytes) in the adult brain. However, the unlimited self-renewal potential of neural stem cells put them in a better position to be the target for malignant transformation in the brain. Our recent work challenged the idea of adult stem cells as the sole source of tumor-initiating potential and generated much controversy in the cancer field by introducing a new concept: tumor reprogramming. We were able to show that glioblastoma can originate from a variety of cells in the brain, including terminally differentiated cortical astrocytes and neurons (Friedmann-Morvinski D. et al, Science 2012). Transduction by oncogenic Cre-inducible lentiviruses in the cortex of SynapsinI-Cre or GFAP-Cre transgenic mice, which drive expression of Cre specifically in neurons and glial cells respectively, induced the formation of gliomas. Interestingly, these tumors mostly expressed markers of progenitor/neural stem cells, Nestin and Sox2.
In a study aimed to follow the kinetic expression of some of these markers during tumor development, we observed that at early stages, differentiation markers are progressively diminished while Nestin, a marker of NSC, undetectable a few days after transduction, increased significantly with tumor progression. We proposed that oncogenic-induced dedifferentiation of mature cells in the brain to a stem/progenitor like state leads to heterogeneous glioma tumors. The genetically acquired plasticity of these cells allows progression and maintenance of this aggressive tumor and even formation of its own blood vessels by transdifferentiation.
Our initial findings identified a transcriptional network with up-regulated genes in three main pathways: Wnt signaling, cell cycle and focal adhesion pathways.
Our future goal is to further elucidate the shared mechanisms between cellular reprogramming and oncogenesis, which may provide innovative insights into oncogenic transformation, tumor heterogeneity, and cancer stem cell origins.
It is clear now that the tumor microenvironment (TME), largely orchestrated by inflammatory cells, is an indispensable player in the neoplastic transformation, supporting proliferation, survival, migration, to mention some of the core hallmarks of cancer. Beyond these hallmarks: what is the contribution of the immune/inflammatory cells to the reprogramming process that we observed in glioma tumors? We assume the dedifferentiation of cancer cells is not a cell autonomous process and stroma cells, including immune/inflammatory cells, may be implicated in supporting this mechanism.
Cancer is not just a mass of malignant cells but a complex “organ”, to which many other cells are recruited and can be corrupted by the transformed cells. Interactions between malignant and non-transformed cells create the tumor microenvironment (TME). The non-malignant cells of the TME have a dynamic and often tumor-promoting function at all stages of carcinogenesis. Intercellular communication is driven by a complex and dynamic network of cytokines, chemokines, growth factors, and inflammatory and matrix remodeling enzymes against a background of major perturbations to the physical and chemical properties of the tissue. The common features of many TMEs suggest that targeting the non-malignant cells, or mediators of their communication, have applications across different tumor types and could also complement other treatment options.
Our goal is to characterize the glioma microenvironment, identify the relevant players and find their contribution to tumor reprogramming and tumor heterogeneity. Our findings will advance the understanding of tumor-stroma interactions, how the TME shapes and promotes tumor development, supporting the notion that the TME is an indispensable player in the neoplastic transformation. Moreover, this analysis will facilitate the development of novel strategies aiming at reprogramming the tumor microenvironment as an additional approach to attack cancer.