Lymphomas develop from immune cells through a stepwise longitudinal process that requires both genetic alterations and a dysregulated immune niche. We are exploring a) the trajectories followed by immune cells undergoing transformation, with a focus on traceable phenotypic changes and key molecular dependencies, and b) accompanying changes in the immune microenvironment that enable or even support cancerous transformation. Through these approaches we aim to develop earlier diagnostic tools focused on pre-malignant stages, and prophylactic  interventions that prevent the overt transformation of immune cells.

The dissemination of lymphomas beyond the lymph nodes and into other organs is associated with very poor prognosis. We are investigating a) how different chemokines influence and guide the movement of tumor cells into distal sites, and b) how epigenetic dysregulation in tumor cells promotes disease spreading. We anticipate our findings will pave the way for the stratification of patients at high risk of dissemination, and the development of therapeutic interventions that block the dissemination of tumor cells.

Some of the most aggressive forms of extranodal lymphomas target "immune privileged" sites, such as the central nervous system and testes. Despite their often-fatal outcome, our understanding of these particular tumors has been largely hindered by a lack of relevant preclinical models. We are developing first-in-kind animal models for these diseases in immune relevant contexts, to enable a better understanding of their pathogenesis, and to developed targeted therapeutic approaches that take into consideration the particular anatomical and microenvironmental contexts of these tumors.

Memory B-cells encompass a diverse collection of specialized cells that enable rapid and enhanced immune responses upon antigen re-exposure, of particular relevance in the context of vaccinations and long-term protection against infections. On the other hand, a subset of memory B-cells appear to play a central role in lymphoma transformation. We are deconvoluting the signaling cascades and molecular mechanisms driving the formation of different subtypes of memory B-cells. We expect this will help us better understand lymphoma pathogenesis, but also inform on better immunization strategies against infectious agents.

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-> ART: One of our seminal studies showed that the most aggressive B cell lymphomas [represented here as a dragon] originate from the cyclic re-entry of memory B-cells [koi fish] into germinal center reactions [central structure], favoring the progressive accumulation of mutations and malignant transformation. Imagery is loosely based on an ancient Japanese tale, where a koi separates from its school, to try to swim up a waterfall. After many attempts, the persistent koi builds enough strength, succeeds, and transforms into a dragon, reflecting its power and strength. (Artist: Gonzalo Greiner)