Grant: Project Grant

Lymphoma is a form of cancer that affects immune cells called lymphocytes, a type of white blood cell. There are many subtypes and maturation stages of lymphocytes and, therefore, many kinds of lymphomas. Diffuse large B-cell lymphomas (DLBCL), the most common type of non-Hodgkin lymphomas, develop from mature B lymphocytes (B-cells) and primarily grow in the lymph nodes. The majority of DLBCL tumors respond to standard therapies, especially if administered in the early stages of the disease. However, one third of patients develop an extranodal form of the disease ("EDLBCL"), where malignant cells spread throughout the body and invade vital organs such as the kidneys, lungs, and brain, significantly reducing chances of survival. There are currently no EDLBCL-specific treatments, and our ability to predict which tumors will disseminate is fairly limited, partly due to a poor understanding of how and when EDLBCL originate. Under normal circumstances, B-cells only expand if and when they encounter external foes, and promptly retract once these are cleared by the immune system. A central unresolved question is then which factors initially drive and further sustain the relentless activation and expansion of B-cells in EDBCL. Based on clinical observations and recent tumor sequencing efforts, we here propose that EDLBCL closely resemble autoimmune disorders, a collection of diseases in which B-cells misidentify natural components of our bodies as threats, leading them to aberrantly activate, infiltrate and attack different organs. We will take advantage of the current extensive knowledge of autoimmune disorders to identify shared players and mechanisms, in an effort to understand how B-cells become cancerous, disseminate, and expand. Our work holds great potential to guide the early identification of patients at high risk of developing EDLBCL and to reveal critical tumor requirements to be harnessed as novel disease-specific therapeutic targets.