About Weizhou Zhang
I have been working on the cancer field for 20 years, starting from my graduate school at the Mount Sinai School of Medicine where I mainly studied signaling pathways involved in cancer progression. I continued breast-cancer research during my postdoctoral fellow in the Karin laboratory at the University of California, San Diego, where I had thorough training on cancer models to study how inflammation and inflammatory signaling impact on cancer progression and metastasis. I started my independent laboratory from July 1st, 2012 at the Department of Pathology, University of Iowa/Carver College of Medicine and explored several new projects critically addressing current clinical complications in cancer progression, prevention and therapy. Our laboratory has been focused on two major directions: 1) how immune system controls or promotes cancer under different pathological or therapeutic conditions; 2) how epithelial cell-intrinsic signaling pathways are altered during cancer development. 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. 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. We further found that these two layers of mammary epithelial cells regulate each other by initiating a paracrine non-canonical Wnt5A signaling that provides inhibitory signal to basal cells under the context of tumor initiation. Our laboratory has expanded in the last several years and one particular fast-growing field is the role DNA repair pathways in cancer therapy. In particular, we have identified that mismatch repair pathway is critical for basal-like breast cancer pathogenesis and progression. Our recent new directions include therapeutic targeting tumor-specific regulatory T cells for cancer immunotherapy using antibodies to target surface proteins or PROTACs to target intracellular proteins. We have found that BCL-XL is a critical survival factor for tumor-specific regulatory T cells and can be inhibited by PROTAC-based degradation. We have several other molecular targets that are being actively explored for potential druggability by PROTACs.
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).
4) The role of TREM-1 in immune regulation and breast cancer metastasis. Dr. Klesney-Tait and our laboratory have been collaborating on this project for several years and yielded outstanding preliminary data to support the current proposal. The two laboratories have distinct yet overlapping interests and expertise that are essential to move this project forward as a team. We will explore the mechanism how TREM-1 contributes to metastasis from innate immune cells to modulate the activity of adaptive immune cells.
In addition, the lab has several novel projects that are under development in renal cancer:
5) Determining the heterogeneity of cancer-infiltrating regulatory T cells using single cell RNA sequencing;
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.
6) Using bioinformatics to define heterogeneity of cancer-infiltrating immune cells from single cells RNA sequencing datasets.
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