Weizhou Zhang,

For more than 25 years, my research has focused on the molecular and cellular mechanisms that drive cancer development, progression, and therapeutic response. My early graduate training at the Mount Sinai School of Medicine centered on elucidating signaling pathways involved in tumor progression. As a postdoctoral fellow in Dr. Michael Karin’s laboratory at the University of California, San Diego, I received comprehensive training in cancer biology and preclinical models, where I investigated the impact of inflammation and inflammatory signaling on tumor growth and metastasis.

Since establishing my independent laboratory in 2012, my research program has addressed key questions in cancer biology through two main directions: (1) understanding how the immune system regulates or promotes tumor progression under various pathological or therapeutic contexts, and (2) investigating how epithelial cell–intrinsic signaling pathways are altered during oncogenesis. My laboratory identified a mechanistic link between obesity and breast cancer progression through macrophage-driven inflammasome and interleukin-1β activation. We also discovered that HER2-driven breast cancers can originate from both luminal and basal mammary epithelial cells and that paracrine noncanonical Wnt5A signaling mediates inhibitory crosstalk between these cell layers during tumor initiation.

More recently, my laboratory has expanded its focus to cancer therapeutics, particularly the role of DNA repair pathways and immune regulation in various cancer types. We have shown that mismatch repair is critical for basal-like breast cancer pathogenesis, are developing novel therapeutic strategies targeting tumor-specific regulatory T cells (Tregs) using antibody-based and PROTAC approaches as new potential cancer immunotherapeutics.

The Zhang Laboratory has long-standing interest in breast cancer-related basic and translational research. The lab has been expanding on several new projects critically addressing current clinical complications in breast-cancer progression, prevention and therapy. The lab has been working on both cancer-cell intrinsic signaling pathways and tumor microenvironment (TME), with special focuses on:

1) How immune system controls or promotes breast cancer under comorbid conditions such as obesity and diabetes etc.;

The first project defined a unique interaction between obesity and breast-cancer progression by stimulating cancer-infiltrating macrophages, and the subsequent inflammasome/interleukin-1beta activation (Publications 5 and 7, funded by a V Scholar Grant from V Foundation for Cancer Research and a R01 Grant from NIH). We continue to understand how inflammasome is activated under obesity and how IL-1β passes obesity-specific signals to neoangiogenesis in cancer.

2) How two layers of mammary epithelial cells interact during normal physiology and breast cancer;

Our research in the 2nd project defines two different populations of cell-of-origins for HER2-induced breast cancer, from both luminal and basal mammary epithelial cells (Publication 2). We identified a novel tumor suppressor CD177 that is expressed on surface of both lineages and inhibits tumorigenesis and relapse (Publication 3, funded by a R01 Grant from NIH). We further found that these two layers of mammary epithelial cells regulate each other by initiating a paracrine none canonical Wnt5A signaling that provides inhibitory signal to basal cells under the context of tumor initiation (Publication 4). We have built strong expertise in the field of breast cancer, inflammation and cancer immunology.

3) How cancer genetics/epigenetics interact with immune system to modulate cancer pathogenesis and immunotherapy.

We have identified that mismatch repair pathway is critical for basal-like breast cancer pathogenesis and progression. Most importantly, we found that genetic inhibition of this DNA repair pathway leads to altered immune cell composition in breast cancer, which could be potentially sensitizing basal like breast cancer to immunotherapy (recently funded by CDMRP, breast cancer breakthrough grant level 1 with Maria Spies with partnering PI).

In addition, the lab has several novel projects that are under development in renal cancer and melanoma:

4) Determining the heterogeneity of cancer-infiltrating regulatory T cells using single cell RNA sequencing and potential targeting Treg cells for cancer immunotherapy.

We have identified CD177 to be expressed by human cancer-infiltrating regulatory T cells. Here we plan to study the genetics of heterogeneous Tregs in human cancer, the role of Tregs in cancer pathogenesis, as well as in immunotherapy. We are currently studying the senescence of TI-Treg cells.

5) In melanoma, we are developing NR4A1 targeting PROTACs for cancer therapy and immunotherapy, funded by a collaborative NCI/R01-funded project.