Targeting actionable liabilities in Merlin-deficient breast cancer

ABSTRACT During tumor progression, loss of cell:cell adhesion and detachment from the extracellular matrix induces dynamic reorganization of the cytoskeleton, formation of invadopodia by the tumor cells, and activation of epithelial-to-mesenchymal transition. This is enabled by tuning molecular programs in order to adapt to loss of

attachment. Merlin, encoded by the NF2 gene, is a member of the ezrin-radixin-moesin protein family that links membrane proteins to the cortical actin cytoskeleton and regulates adhesion, migration, cell-cell contact, proliferation, and signal transduction. Merlin is critically involved in contact-dependent inhibition of growth.

We found that Merlin protein levels are reduced in the majority of cases of infiltrating ductal carcinoma and metastatic breast cancer tissues. Decreased Merlin protein expression was also seen with advanced nodal involvement in breast cancer. In order to ascribe clinical relevance, we re-capitulated the loss of Merlin in breast

cancer cells. Merlin deficiency elicited a markedly invasive phenotype, morphologically and programmatically evident as epithelial-to-mesenchymal transition. In order to overcome the challenge of embryonic lethality of a total Nf2-knockout, we generated a unique mammary-specific Nf2-knockout mouse mammary tumor model.

These mice show remarkably accelerated development of tumors.

In this R21 application, our objective is to target potential liabilities in Merlin-deficient mammary tumors to mitigate their metastasis-conducive tumor portfolio. Using multiple Merlin-deficient mammary tumor systems and tumor- derived organoids, we will investigate (i) targeting aberrantly activated Hh signaling in Merlin-deficient tumors,

and (ii) the potential to target deregulated tryptophan metabolism in Merlin-deficient tumors. Our approaches are non-overlapping and complementary. Outcomes from our work will present two unprecedented strategies to target possible liabilities in Merlin-deficient breast cancer; these findings can be expanded and/or translated to

other tumor types that harbor Merlin deficiency.