A role for the MALT1 substrate Tensin-3 in lymphoma dissemination

What is it about?

Chronic activation of B-cell receptor (BCR)-dependent signaling is a characteristic shared by certain aggressive lymphomas. Constitutive BCR signaling activates the protein MALT1, an enzyme that promotes the proliferation of lymphoma cells. Several substrates of MALT1 have been described; these play major roles in modulating BCR-induced transcriptional responses. Our new work identifies a protein called Tensin-3 as a MALT1 substrate. Tensin-3 was known to act as a bridge between integrins and the actin cytoskeleton, and to control the adhesion of epithelial cells by contributing to the formation of the focal adhesion complex. In our study we show that Tensin-3 is expressed in B cells and becomes cleaved upon B-cell activation. Moreover, we show that Tensin-3 undergoes constitutive cleavage in BCR-driven, aggressive B-cell lymphoma models. In contrast to cleavage of other known MALT1 substrates, Tensin-3 cleavage has no impact on cell proliferation or transcriptional activation. Instead, it leads to reduced cellular adhesion and increased metastatic dissemination of lymphoma cells to the bone marrow and spleen. Thus, MALT1-dependent Tensin-3 cleavage unveils a new aspect of the function of MALT1, which is to promote metastatic dissemination of B-cell lymphomas by negatively regulating integrin-dependent B-cell adhesion.

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Photo by National Cancer Institute on Unsplash

Photo by National Cancer Institute on Unsplash

Why is it important?

Our research demonstrates a novel facet of MALT1 biology by revealing that MALT1 cleaves Tensin-3, thereby limiting the adhesion of activated B cells and promoting metastatic lymphoma dissemination. These findings are significant given how aggressive these tumors are and how commonly they manifest extra-nodal dissemination. Therefore, therapeutic targeting of the enzyme MALT1 may not only help to limit tumor proliferation, by reducing gene transcription, but additionally limit lymphoma aggressiveness by diminishing metastasis.