THE MULLER LAB
PUBLICATIONS
Nothing but "NETs"
to cure cancer
T cell exclusion to the margins and stroma of solid tumors represents a mechanism of resistance to immunotherapies. Herein, we describe that tumor Stat3 drives expression of the immunosuppressive cytokine known as Chi3l1 in human triple-negative breast cancers as well as mouse models. We identified that Chi3l1 directly acts on neutrophils promoting their recruitment and inducing generation of neutrophil extracellular traps (NETs) that prevent T cell infiltration into the tumor nest. Targeting Chi3l1 may be a viable mechanism for improving T cell infiltration and reinvigorating response to immunotherapy.
HER2Δ16 and ENPP1 in breast cancer progression
HER2+ breast cancer represents an aggressive form of breast cancer that relies heavily on an immunotherapy bases regimens (Trastuzumab/Pertuzumab) for its clinical management. In our new mouse models that express either wildtype HER2 or an activated splice isoform known as HER2(delta)16, the latter drives formation of an immune cold microenvironment characterized by poor T cell infiltration and upregulation of immunosuppressive cytokines. Cell surface proteome profiling of the cancer cells identified ENPP1 to be selectively upregulated on HER2(delta)16+ cancer cells. Targeting ENPP1 leads to improved T cell infiltration.
Epigenetic regulation during breast cancer initiation
Our findings suggest that Ezh2 plays a crucial role in integrating the mTORC1 and Wnt signaling pathways to initiate mammary tumor progression. Specifically, loss of Ezh2 up-regulated genes involved in suppressing these pathways. Notably, Sfrp1, a negative regulator of Wnt signaling, was up-regulated in Ezh2-deficient epithelium, and its expression was associated with favorable clinical outcomes in luminal B subtype patients.