Model of a MALT1-Dependent Signaling Cascade Driving Endothelial Permeability
The Lucas / McAllister laboratory focuses on a complex of signaling proteins referred to as the CARMA-Bcl10-MALT1 (CBM) signalosome. The Lucas / McAllister group, along with several other laboratories around the world, first discovered this CARMA-Bcl10-MALT1 (CBM) signalosome because the genes encoding with its components are targeted by mutation and chromosomal mutation in lymphoid malignancy. The CBM signalosome plays a critical role in normal lymphocyte function by mediating receptor-dependent activation of the proinflammatory, pro-survival NF-κB transcription factor.
The laboratory has gone on to make major contributions in the understanding the mechanisms by which deregulation of the CBM complex promotes B-cell non-Hodgkin lymphoma. The group discovered that the API2-MALT1 fusion oncoprotein possesses unique gain-of-function MALT1 proteolytic activity that drives the proliferation and survival of malignant B-cells (Science, 2011;331:468-72 and Nature Communications, 2015;6:5908). The group is now also focusing on the mechanisms by which deregulated MALT1 activity promotes diffuse large B-cell lymphoma. The CARMA-Bcl10-MALT1 Signaling Complex in Inflammatory and Neoplastic Disease. The team discovered that a CBM signalosome also functions outside of lymphocytes by operating downstream of specific G-protein coupled receptors (GPCRs) in non-immune cells. In this case, the nonlymphoid-specific homologue CARMA3 substitutes for the lymphocyte-specific CARMA1.
The laboratory is actively studying the contribution of GPCR-induced, CBM dependent stimulation of NF-κB to a variety of inflammatory and neoplastic diseases and exploring the utility of inhibiting the CBM complex as a new approach for the treatment of these conditions. Specifically, the researchers have elucidated a new role for the CBM complex in mediating progression and metastasis of a variety of solid tumors, including breast cancer and sarcoma. The work was recently accepted for publication in the high-impact journal Cancer Research. In addition, the Lucas / McAllister research group has discovered a new role for MALT1 proteolytic activity in promoting GPCR induced endothelial permeability, a finding that was recently published in and featured on the cover of Cell Reports.
The Lucas / McAllister Laboratory is co-directed by Linda McAllister-Lucas MD, PhD, Division Chief of the Department of Hematology/Oncology, and Peter Lucas MD, PhD, faculty in the Department of Pathology. The lab includes twelve scientists at varying stages of training.