Dinis Calado


Interplay between immunity and cancer development

A major interest of the Immunity and Cancer Lab is to understand how healthy cells become cancerous. To address this question we study B cells which provide a great model system given that their normal development is well defined. B cells, an essential cellular component of the immune system develop from hematopoietic stem cells in the bone marrow through a highly regulated process which results in the production of functional mature B cells. During the course of a T cell dependent immune response, mature B cells encounter antigen and further develop in peripheral tissues, like spleen and lymph nodes, into memory B cells or terminally differentiate into plasma cells (antibody secreting cells) in a reaction called germinal centre (GC) [1]. It is known that cancer cells may arise from healthy B cells at several stages of development, however cancers derived from mature B cells predominate and are in their vast majority derived from B cells undergoing a GC reaction [1]. These cancers include the aggressive Burkitt [2] and Diffuse Large B cell lymphomas [3,4] as well as Multiple Myeloma (a plasma cell cancer), which is currently incurable.

Using an integrative approach to immunology and cancer biology the projects in the Lab include:

(i)         Identify and study subpopulations within healthy B cells undergoing a GC reaction, which due to their physiology are at a particularly high risk of becoming cancer cells, i.e. "cells of origin in cancer" [5],

(ii)        Investigate the causative mutations, including the study of non-coding RNAs, responsible for the progressive process of how a healthy B cell develops into a cancer cell [2,3],

(iii)       Assess the processes of evasion of cancer cells from immune control by determining the nature of the interplay between a developing B cell cancer and cells of the immune system e.g. FoxP3pos regulatory T cells.

To perform these studies the Lab takes advantage of inter-species comparisons. We have in place cutting-edge genetic techniques to address these questions in vivo in the mouse, including conditional gain-of-function and/or loss-of-function specifically in the B cell subsets of interest using primarily the Cre-LoxP system [2,3,4,5]. The confirmation and/or validation of the findings in these systems are obtained through the study of human samples of mature B cell derived cancers.

These are examples of the sorts of project, which might be available in this research group. Only one studentship is available with this group and the precise project will be decided on consultation with the supervisor.

1. Klein, U. and Dalla-Favera, R. (2008)
Germinal centres: role in B-cell physiology and malignancy.
Nature Reviews Immunology 8: 22-33. PubMed abstract

2. Sander, S., Calado, D. P., Srinivasan, L., Köchert, K., Zhang, B., Rosolowski, M., Rodig, S. J., Holzmann, K., Stilgenbauer, S., Siebert, R., Bullinger, L. and Rajewsky, K. (2012)
Synergy between PI3K signaling and MYC in Burkitt lymphomagenesis.
Cancer Cell 22: 167-179. PubMed abstract

3. Calado, D. P., Zhang, B., Srinivasan, L., Sasaki, Y., Seagal, J., Unitt, C., Rodig, S., Kutok, J., Tarakhovsky, A., Schmidt-Supprian, M. and Rajewsky, K. (2010)
Constitutive canonical NF-κB activation cooperates with disruption of BLIMP1 in the pathogenesis of activated B cell-like diffuse large cell lymphoma.
Cancer Cell 18: 580-589. PubMed abstract

4. Zhang, B., Calado, D. P., Wang, Z., Fröhler, S., Köchert, K., Qian, Y., Koralov, S. B., Schmidt-Supprian, M., Sasaki, Y., Unitt, C., Rodig, S., Chen, W., Dalla-Favera, R., Alt, F. W., Pasqualucci, L. and Rajewsky, K. (2015)
An oncogenic role for alternative NF-κB signaling in DLBCL revealed upon deregulated BCL6 expression.
Cell Reports 11: 715-726. PubMed abstract

5. Calado, D. P., Sasaki, Y., Godinho, S. A., Pellerin, A., Kochert, K., Sleckman, B. P., de Alborán, I. M., Janz, M., Rodig, S. and Rajewsky, K. (2012)
The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers.
Nature Immunology 13: 1092-1100. PubMed abstract