Modeling B cell lymphomas to understand the biological principles of cancer initiation
Cancer initiation is believed to shape the molecular and cellular landscape of cancer. In most cancer types, initiation is triggered by acquisition of a first pro-oncogenic event (for example, a chromosomal translocation), which is followed by the stepwise accumulation of many other additional genetic abnormalities. The heterogeneous repertoire of mutations in each cancer results in complex cellular architectures, built by multiple genetically distinct subclones that will largely define the biology and clinical features of the disease. Such heterogeneity endows tumors with the ability to progress, resist targeted therapies, and relapse. These distinct genotypic features could conversely be used to trace the disease in individuals at risk and for its early detection, when treatment would be most effective.
Our laboratory is interested in exploring the interplay between oncogenes, the cellular context, and tissue dynamics during cancer initiation and, more specifically, B cell lymphomagenesis. We are also studying how these events shape disease evolution at the cellular and genomic level. To address these questions we use tailored in vitro, ex-vivo, and in vivo methodologies that exploit the experimental synergies occurring at the intersection between cancer biology, developmental biology, and immunology. With this, we seek to refine our knowledge on the cellular origin of B cell lymphomas and the basic principles of cancer initiation, as a means to ultimately improve our current understanding of the disease and to conceive unprecedented strategies aimed at both its prevention and safe eradication.
We focus our work around models of MYC-dependent B cell lymphomagenesis. MYC is a well-known proto-oncogene, often deregulated in human cancer, and endowed with the ability to promote autonomous cell growth and trigger DNA damage when deregulated. MYC gene rearrangements act as initiating events in the natural history of many aggressive cancer types, including B cell lymphomas and leukemias, and promote cancer when engineered in animal models, though only upon acquisition of additional genetic lesions. MYC-dependent lymphomagenesis is therefore a natural model to study the evolution of genetic and clonal heterogeneity during cancer progression and the role of oncogenes in this process. The B lymphoid compartment is a highly dynamic environment, both at cellular and genomic level, for which we have acquired extensive knowledge on the developmental, cellular, and molecular aspects. With this, lymphomagenesis constitutes a unique model to dissect the complexity of cancer into simple conceptual and mechanistic elements.
Our work is/has been supported by generous financial support from the following sources:
National Institutes of Health / National Cancer Institute
Louis Sklarow Memorial Trust
Leukemia Research Foundation
National Cancer Center