Research

The Oncoimmune Lab at Mayo Clinic has several ongoing research projects.

The CBM signalosome in non-Hodgkin lymphoma

Early in their careers, Drs. Lucas and McAllister made a series of critical discoveries that led to a new understanding of the molecular mechanisms responsible for driving non-Hodgkin lymphoma. Specifically, our team characterized a novel signaling complex composed of the proteins CARMA1, BCL10 and MALT1, now called the CBM signalosome.

We found that the CBM signalosome normally functions as a cornerstone of the immune system and plays a critical role in adaptive immunity by mediating antigen-induced NF-kB activation and proliferation of T and B lymphocytes. However, we also discovered that the activity of the CBM signalosome can be dysregulated by gain-of-function mutations and gene fusions.

In particular, genomic alterations that affect the CBM components or upstream signaling molecules that connect the CBM signalosome to the antigen receptor can lead to unregulated NF-kB activation and uncontrolled proliferation. These alterations serve as driver mutations for a significant percentage of cases of activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), MALT lymphoma, and several other subtypes of non-Hodgkin lymphomas and leukemias. This finding highlights the central role of the CBM signalosome in the pathogenesis of lymphoid neoplasms.

Our lab team continues to study the CBM signalosome. We're now focusing on approaches to specifically target CBM activity by developing novel small molecule therapeutics to disrupt assembly of the signalosome in ABC-DLBCL.

Related publications:

• A small-molecule inhibitor of BCL10-MALT1 interaction abrogates progression of diffuse large B cell lymphoma.
• GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein.
• Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-κB activation.

The CBM signalosome in breast cancer

We recently discovered that the CBM signalosome is active in some solid tumors, including triple-negative breast cancer. This is one of the most aggressive forms of breast cancer and a type that lacks effective approaches for targeted therapy.

In this setting, the CBM signalosome is not driven by known specific mutations in the CBM components. Rather, it's driven by hyperactivation of a series of overexpressed cell surface receptors that include the receptors for thrombin (PAR1), angiotensin (AGTR1) and lysophosphatidic acid (LPAR).

Our Oncoimmune Lab team is studying how hyperactivation of the CBM signalosome in triple-negative breast cancer drives upregulation of the immune checkpoint protein PD-L1 and promotes the secretion of multiple immunosuppressive factors that together impair the activity of neighboring immune cells.

Related publications:

• MALT1 is a targetable driver of epithelial-to-mesenchymal transition in claudin-low, triple-negative breast cancer.
• MALT1 is a critical mediator of PAR1-driven NF-κB activation and metastasis in multiple tumor types.
• The CARMA3-Bcl10-MALT1 signalosome drives NFκB activation and promotes aggressiveness in angiotensin II receptor-positive breast cancer.

HER2-positive breast cancer

One of our newest areas of investigation centers around our discovery that a truncated form of the HER2 oncoprotein, called p95HER2, drives a potent immunosuppressive program in the setting of HER2-positive breast cancer. This work is being conducted as Project 4 within the Mayo Clinic Breast Cancer SPORE.

The p95HER2 protein is produced as an alternative translation product from a noncanonical Kozak sequence within the same mRNA that encodes the full-length HER2 protein. As such, the p95HER2 protein may be expressed in concert with the full-length HER2 protein in some cases of HER2-positive breast cancer. The mechanisms governing its relative expression are still poorly understood and are being actively investigated.

Importantly, our research team discovered that p95HER2 signals differently from the full-length HER2 protein and engages signaling pathways that are critical for upregulation of PD-L1 and numerous immunosuppressive molecules.

Based on these discoveries, our team is working to develop a clinically viable assay for p95HER2 expression in breast cancer. In addition, we're working with clinical colleagues in the Breast Cancer Disease Group of Mayo Clinic Comprehensive Cancer Center to launch a clinical trial to specifically target p95HER2 and restore antitumor immunity in cases of HER2-positive cancer where upregulation of p95HER2 is identified.

Related publications:

• P95HER2, a truncated form of the HER2 oncoprotein, drives an immunosuppressive program in HER2+ breast cancer that limits trastuzumab deruxtecan efficacy.

Brain cancer and liver cancer

Our other projects center on the role of MALT1 signaling in glioblastoma, a type of brain cancer, and in hepatocellular carcinoma, the most common form of liver cancer.

Our brain cancer work is being conducted in collaboration with Oncoimmune Lab team members Juliana Yerneni, Ph.D., and Sai Yerneni, Ph.D. This research seeks to understand the role of the CBM signalosome in macrophages and microglial cells of the brain cancer microenvironment.

The liver cancer project represents an innovative offshoot of work by team member Dong Hu, Ph.D. This work is based on his discovery of a new role for MALT1 in mediating signal transduction independently of the CBM signalosome via engagement of the anti-viral RIG-I/MAVs pathway.

Related publications:

• MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression.
• Bcl10 links saturated fat overnutrition with hepatocellular NF-kB activation and insulin resistance.