Lymphomas are a group of cancers that affect cells in our immune system called lymphocytes. Diffuse large B-cell lymphomas, the most common type of lymphoma in adults, develop from B lymphocytes (B cells), and typically grow in the lymph nodes nodes (small, bean-shaped organs that filter substances in our bodies). When these tumors are detected and treated in their early stages, most patients can be fully cured. However, one third of patients develop a form of the disease where tumor cells spread throughout the body and start growing in critical organs such as the kidneys, lungs, and even the brain. Treatments are much less effective in these cases, resulting in lower chances of survival. To worsen the situation, there is no way of anticipating which tumors will spread, and even if there was, there are no treatments that could block this process.

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 lymphomas that grow outside of the lymph nodes. Based on clinical observations and recent tumor sequencing efforts, we propose that tumors growing outside of the lymph nodes 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 are taking 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 this aggressive lymphomas, and to reveal critical tumor requirements to be harnessed as novel disease-specific therapeutic targets.

Our team set out on a quest to identify components of lymphoma cells that would allow them to spread throughout the body. In doing so, we found a protein that starts accumulating in B cells before tumors fully develop and spread. This protein is absent from healthy B cells, but helps other lymphocytes travel to different organs to complete their protective function. We think that some lymphoma cells find a way to build up large amounts of this protein and use this to support their malignant spread. We aim to a) determine if lymphoma spread can be prevented using drugs against this protein, b) understand what type of messages lymphoma cells get from this protein, and c) assess if measuring this protein in tumors could flag those more likely to spread. To do so, we will study samples routinely collected from lymphoma patients at time of diagnosis, and test treatments in animal models. This project could set the stage for the early identification of lymphoma patients at risk of developing an aggressive form of the disease, and discover a way to treat them to prevent an often-fatal event.

In a small number of cases, lymphomas first develop in the testes. Standard treatment for these lymphomas involves surgery, in which both the tumor and the affected testicle(s) are removed. This is followed by radiation and chemotherapy, to try to kill any leftover tumor cells. Unfortunately, this strategy is not very effective. This means that, in at least half of the cases, tumors grow back in the other testicle and/or in vital organs, including the brain. At this stage, additional treatment options are limited, and most patients succumb to the disease within months. There is then an urgent need to develop better treatments, and tools to identify those patients in which tumors are more likely to grow back. For this to happen, we first need to understand the disease better. This typically requires studying a large number of tumor samples, collected at time of surgery. However, given that testicular lymphomas are fairly uncommon, it may take decades to secure enough samples to run such studies, even at large cancer centers. 
An alternative strategy that has proven extremely useful to study other lymphomas, is the use of preclinical models. These are simplified systems (generally animal or cell based) that mimic one or more key characteristics of the human disease. We are using all the information available to date on the disease, to develop the first models of testicular lymphoma. These models will allow us and others to explore in detail how the disease originates, and how it behaves during and after treatment. This knowledge, in turn, is expected to guide the development of new therapies, specific to testicular lymphomas. The same models could further be used to run initial tests on therapies, to help select the most promising candidates to advance to the clinic. In all, we expect our work to make a significant contribution to improving outcomes for patients with this rare but aggressive cancer type.

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-> ART: Artistic rendering of a normal immune cell [represented here as a koi fish] transforming into a cancerous cell [represented here as a dragon]. Our previous work showed that lymphomas take a long time to develop, and depend on immune cells being able to jump multiple "hurdles" that our body sets in place to protect us from cancerous transformation. Imagery is loosely based on an ancient Japanese tale, where a koi decided to separate 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. (Artist: Gonzalo Greiner)