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Research
Function of MDSCs in metastatic TNBC
TNBC is one of the most aggressive forms of breast cancer and is associated with a very high mortality rate. Treatment of TNBC patients is particularly challenging due to the heterogeneity of the disease and plasticity of the cancer cells. Using tumor samples from breast cancer patients, our lab has demonstrated for the first time an increased abundance of (myeloid derived suppressor cells) MDSCs, a type of immune cells in breast tumor microenvironment (TME) of human TNBC patients compared to luminal (non-TNBC) patients (Journal of Clinical Investigation, 2018). Intriguingly, we found that high levels of Np63, a transcription factor that we initially identified as an important driver of basal /TNBC breast cancer (Nature Cell Biology, 2014), correlates with greater numbers of MDSCs in the TME of TNBC and also drives tumor growth, progression and metastasis. We are currently testing how these MDSCs are modulating function of cancer cells in advanced stage metastatic TNBC. Secreted factors from MDSCs are being evaluated for their pro-tumorigenic function. New untargeted lipidomics data have highlighted the connection of lipid metabolism of MDSCs to aggressive nature of TNBC and metastasis, which is currently being investigated in the laboratory as well.
Paradoxical function of Interferon gamma signaling in breast cancer
Interferons (IFNs) were originally hailed as miracle drugs for the treatment of cancer and Interferon gamma (IFN-γ), a type II interferon, showed some therapeutic promise, several newer clinical studies revealed that IFN-γ significantly increased mortality in cancer patients receiving adjunct recombinant protein therapy. Moreover, it is now clear that while IFN-γ has significant anti-tumorigenic effects, it can also promote tumor cell evasion and progression in many cancers, including melanoma, peritoneal cancer, gastric cancer etc. Our new studies (Nature Cell Biology, 2020) in a novel TNBC model suggest that IFN-γ treatment significantly increases the metastasis and tumor growth of TNBC. Current work focuses on determining targets of pro-tumorigenic IFN-γ signaling such as PD-L1 and others in TNBC. Although initial studies show that stabilized IFNGR1 in tumor cells is partly responsible for IFN-γ signaling, the source of IFN-γ is yet to be identified. Thus, we are also very interested to identify what immune cells secreting IFN-γ are responsible for tumor progression and metastasis and if depleting them or inhibiting their function may lead to reduced tumor progression. These studies will help identify new biomarkers for aggressive TNBC and will also shed light on potential new drug targets for these subset of patients.
Tumor Macrophages in drug resistance of breast cancer
Notch signaling is highly conserved across many species and regulates cell proliferation, cell fate, differentiation, and cell death. In a very exciting study, we showed that a novel Notch signaling ligand, DLL1, is highly expressed in MaSCs and is important for MaSC number and function (Science, 2018). Furthermore, we showed that DLL1 helps to maintain the macrophageal niche of the mammary gland, which differ from other tissue macrophages in that they secrete high Wnt factors that are required for the survival of MaSCs. This study provided the first evidence that macrophages play a nurturing role within the normal MaSC niche by activating Wnt signaling in stem cells. To further understand the function of DLL1 in breast cancer, we made several mouse and xenograft models and found that in DLL1 is important for Estrogen receptor+ (ER+) luminal breast cancer progression and metastasis, and is also responsible for driving chemo resistance (Oncogene, 2018 and Nature Communication, 2021). Currently, we are investigating the molecular mechanism of Dll1 mediated Notch signaling on chemo resistance and other drug resistances such as endocrine and radioresistance. Particularly, we are focusing on crosstalk between tumor macrophages and cancer fibroblasts with tumor cells in tumor to delineate the process of acquiring resistance.