Weizhou Zhang

Weizhou Zhang,

ASO PROF

Department: MD-PATHOLOGY-GENERAL
Business Phone: (352) 273-6748
Business Email: zhangw@ufl.edu

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.

Accomplishments

Dr. and Mrs. James Robert Spencer Professor of Pathology
2019-Current · University of Florida, Gainesville, FL
The V Scholar Award
2014-2016 · The V Foundation for Cancer Research
NIH Pathway to independence award
2011-2015 · National Cancer Institute at the National Instistues of Health
Postdoctoral Fellowship Award
2008-2011 · Susan G. Komen for the Cure
Postdoctoral Fellowship Award
2006-2007 · Health Research Science Board of New York State Department of Health
Liu Yong-Lin Scholarship for Excellence in Scientific Research
2001 · Chinese Academy of Sciences, China
Outstanding Graduate with Award of Top One Scholarship
2001 · Institute of Microbiology, Chinese Academy of Sciences, China
Outstanding Graduate
1998 · The Nankai University

Research Profile

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.

Open Researcher and Contributor ID (ORCID)

0000-0002-8236-0346

Publications

2021
AP-2γ Is Required for Maintenance of Multipotent Mammary Stem Cells.
Stem cell reports. 16(1):106-119 [DOI] 10.1016/j.stemcr.2020.12.002. [PMID] 33382976.
2021
BCL11B is positioned upstream of PLZF and RORγt to control thymic development of mucosal-associated invariant T cells and MAIT17 program.
iScience. 24(4) [DOI] 10.1016/j.isci.2021.102307. [PMID] 33870128.
2021
Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy.
Science translational medicine. 13(604) [DOI] 10.1126/scitranslmed.abc8922. [PMID] 34321321.
2021
Body fatness and breast cancer risk in relation to phosphorylated mTOR expression in a sample of predominately Black women.
Breast cancer research : BCR. 23(1) [DOI] 10.1186/s13058-021-01458-z. [PMID] 34330319.
2021
Mapping the immune environment in clear cell renal carcinoma by single-cell genomics.
Communications Biology. 4(1) [DOI] 10.1038/s42003-020-01625-6. [PMID] 33504936.
2021
Proteolysis-targeting chimera against BCL-XL destroys tumor-infiltrating regulatory T cells
Nature Communications. 12(1) [DOI] 10.1038/s41467-021-21573-x. [PMID] 33627663.
2021
The Diagnostic Performance of Early Sjögren’s Syndrome Autoantibodies in Juvenile Sjögren’s Syndrome: The University of Florida Pediatric Cohort Study.
Frontiers in immunology. 12 [DOI] 10.3389/fimmu.2021.704193. [PMID] 34249010.
2021
Understanding and Targeting Human Cancer Regulatory T Cells to Improve Therapy
Advances in Experimental Medicine and Biology. 1278:229-256 [DOI] 10.1007/978-981-15-6407-9_12. [PMID] 33523451.
2020
Cancer cell-intrinsic function of CD177 in attenuating β-catenin signaling.
Oncogene. 39(14):2877-2889 [DOI] 10.1038/s41388-020-1203-x. [PMID] 32042113.
2020
CD177 at the crossroads of adherens junction and -Catenin activation
Oncogene.
2020
Contribution of synergism between PHF8 and HER2 signalling to breast cancer development and drug resistance
Ebiomedicine. 51 [DOI] 10.1016/j.ebiom.2019.102612. [PMID] 31923801.
2020
IL-1 Signaling in Tumor Microenvironment.
Advances in experimental medicine and biology. 1240:1-23 [DOI] 10.1007/978-3-030-38315-2_1. [PMID] 32060884.
2020
Obesity and Breast Cancer: A Case of Inflamed Adipose Tissue.
Cancers. 12(6) [DOI] 10.3390/cancers12061686. [PMID] 32630445.
2019
A TFAP2C Gene Signature is Predictive of Outcome in HER2-positive Breast Cancer
Molecular Cancer Research. 18(1):46-56 [DOI] 10.1158/1541-7786.MCR-19-0359. [PMID] 31619506.
2019
DT2216, a BCL-XL proteolysis targeting chimera, is a safer and more potent antitumor agent than ABT263
. 25(12):1938-1947
2019
Exceptional responses with sequential metronomic temozolomide after pembrolizumab failure in patients with metastatic melanoma
Melanoma research. 29(6):643-647 [DOI] 10.1097/CMR.0000000000000592. [PMID] 30829928.
2019
Identification of novel TGF-beta regulated genes with pro-migratory roles
Biochimica et biophysica acta. Molecular basis of disease (Online). [DOI] 10.1016/j.bbadis.2019.165537.
2019
Identification of novel TGF-β regulated genes with pro-migratory roles
Biochimica Et Biophysica Acta-Molecular Basis of Disease. 1865(12) [DOI] 10.1016/j.bbadis.2019.165537. [PMID] 31449970.
2019
Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4.
Oncogene. 38(13):2351-2363 [DOI] 10.1038/s41388-018-0592-6. [PMID] 30518876.
2019
Off-Target Deletion of Conditional Dbc1 Allele in the Foxp3YFP-Cre Mouse Line under Specific Setting.
Cells. 8(11) [DOI] 10.3390/cells8111309. [PMID] 31652947.
2019
ROR1 Potentiates FGFR Signaling in Basal-Like Breast Cancer.
Cancers. 11(5) [DOI] 10.3390/cancers11050718. [PMID] 31137681.
2019
Single-cell profiling of cutaneous T-cell lymphoma reveals underlying heterogeneity predicting with disease progression
Clinical Cancer Research. 25(10):2996-3005 [DOI] 10.1158/1078-0432.CCR-18-3309. [PMID] 30718356.
2018
A novel HER2 gene-body enhancer contributes to HER2 expression
Oncogene. 37(5):687-694 [DOI] 10.1038/onc.2017.382. [PMID] 29035388.
2018
Keeping Tumors in Check: A Mechanistic Review of Clinical Response and Resistance to Immune Checkpoint Blockade in Cancer.
Journal of molecular biology. 430(14):2014-2029 [DOI] 10.1016/j.jmb.2018.05.030. [PMID] 29800567.
2018
Reevaluating E-Cadherin and B-Catenin: a pan-cancer proteomic approach with an emphasis on breast cancer
The American Journal Of Pathology. 188(8):1910-1920 [DOI] 10.1016/j.ajpath.2018.05.003. [PMID] 29879416.
2018
Stabilization of NF-kB-inducing kinase suppresses MLL-AF9-induced acute myeloid leukemia
Cell Reports. 22(2):350-458 [DOI] 10.1016/j.celrep.2017.12.055. [PMID] 29320732.
2018
The clinical promise of immunotherapy in triple-negative breast cancer
Cancer Management and Research. Volume 10:6823-6833 [DOI] 10.2147/cmar.s185176.
2018
The clinical promise of immunotherapy in triple-negative breast cancer.
Cancer management and research. 10:6823-6833 [DOI] 10.2147/CMAR.S185176. [PMID] 30573992.
2018
TRGAted: A web tool for survival analysis using protein data in the Cancer Genome Atlas
F1000Research. 7 [DOI] 10.12688/f1000research.15789.1. [PMID] 30345029.
2017
Genetic enhancement in cultured human adult stem cells conferred by a single nucleotide recoding
Cell Research. 27(9):1178-1181 [DOI] 10.1038/cr.2017.86. [PMID] 28685772.
2017
Histone demethylase PHF8 promotes epithelial to mesenchymal transition and breast tumorigenesis
Nucleic acids research. 45(4):1687-1702 [DOI] 10.1093/nar/gkw1093. [PMID] 27899639.
2017
Visualization of aging-associated chromatin alterations with an engineered TALE system.
Cell research. 27(4):483-504 [DOI] 10.1038/cr.2017.18. [PMID] 28139645.
2016
Involvement of the NLRC4-Inflammasome in Diabetic Nephropathy.
PloS one. 11(10) [DOI] 10.1371/journal.pone.0164135. [PMID] 27706238.
2016
NLRC4 suppresses melanoma tumor progression independently of inflammasome activation
The Journal Of Clinical Investigation. 126(10):3917-3928 [DOI] 10.1172/JCI86953. [PMID] 27617861.
2016
Obesity and cancer: inflammation bridges the two.
Current opinion in pharmacology. 29:77-89 [DOI] 10.1016/j.coph.2016.07.005. [PMID] 27429211.
2016
Obesity-associated NLRC4 inflammasome activation drives breast cancer progression.
Nature communications. 7 [DOI] 10.1038/ncomms13007. [PMID] 27708283.
2016
SIRT6 safeguards human mesenchymal stem cells from oxidative stress by transactivating NRF2
Cell Research. 26(2):190-205 [DOI] 10.1038/cr.2016.4. [PMID] 26768768.
2016
Vitamin C alleviates aging defects in a stem cell model for Werner syndrome
Protein & cell. 7(7):478-488 [DOI] 10.1007/s13238-016-0278-1. [PMID] 27271327.
2015
Bone marrow stromal antigen 2 (BST-2) DNA is demethylated in breast tumors and breast cancer cells
PLoS One. 10(4)
2015
Characterization of a novel mouse model with genetic deletion of CD177
. 6(2):117-126
2015
Paracrine WNT5A signaling in healthy and neoplastic mammary tissue
Molecular & cellular oncology. 3(1) [DOI] 10.1080/23723556.2015.1040145. [PMID] 27308558.
2015
Paracrine Wnt5a signaling inhibits the expansion of tumor-initiating cells
Cancer research. 75(10):1972-1982 [DOI] 10.1158/0008-5472.CAN-14-2761. [PMID] 25769722.
2015
PTEN deficiency reporgrammes human neutral stem cells towards a glioblastoma stem cell-like phenotype
Nature Communications. 6 [DOI] 10.1038/ncomms10068. [PMID] 26632666.
2015
TFAP2C governs the luminal epithelial phenotype in mammary development and carcinogenesis
Oncogene. 34(4):436-444
2015
The Role of Tcfap2c In Tumorigenesis and Cancer Growth in an Activated Neu Model of Mammary Carcinogenesis
Oncogene. 34(50):6105-14 [DOI] 10.1038/onc.2015.59. [PMID] 25772240.
2015
Transcriptome analysis of basal and luminal tumor-initiating cells in ErbB2-driven breast cancer.
Genomics data. 4:119-122 [PMID] 26167451.
View on: PubMed
2014
Inflammasomes in cancer: a double-edged sword.
Protein & cell. 5(1):12-20 [DOI] 10.1007/s13238-013-0001-4. [PMID] 24474192.
2014
NIAM-deficient mice are predisposed to the development of proliferative lesions including B-cell lymphomas
PLoS One. 9(11)
2014
ROR1, an embryonic protein with an emerging role in cancer biology
. 5(7):496-502
2014
Ubc13 controls breast cancer metastasis through a TAK1-p38 kinase cascade
. 111(38):13870-13875
2013
A NIK-IKK module expands ErbB2-induced tumor- initiating cells by stimulating nuclear export of p27/Kip1
Cancer cell. 23(5):647-659 [DOI] 10.1016/j.ccr.2013.03.012. [PMID] 23602409.
2013
An IKKα-E2F1-BMI1 cascade activated by infiltrating B cells controls prostate regeneration and tumor recurrence
. 27(13)
2013
Beneficial and detrimental roles of NLRs in carcinogenesis
Frontiers in immunology. 4 [DOI] 10.3389/fimmu.2013.00370. [PMID] 24273542.
2013
DNA methylome: Unveiling your biological age
Protein and Cell. 4(10):723-725
2013
Magnetic field activated lipid-polymer hybrid nanoparticles for stimuli-responsive drug release
Acta Biomaterialia. 9(3):5447-5452
2013
Switching cell fate, ncRNAs coming to play
. 4
2013
TET on
Cell research. 23(7):863-865 [DOI] 10.1038/cr.2013.72. [PMID] 23732523.
2013
Top Notch cancer stem cells by paracrine NF-κB signaling in breast cancer
Breast Cancer Research. 15(5)
2012
Converted Neural cells: induced to a cure?
Protein & cell. 3(1):1-7 [DOI] 10.1007/s13238-012-2029-2. [PMID] 22410787.
2012
Externally triggered on-demand drug release and deep tumor penetration
Journal of Vacuum Science & Technology B. 30(2)
2012
Find and Replace: editing human genome in pluripotent stem cells
Protein and Cell. 2(12):950-956 [DOI] 10.1007/s13238-011-1132-0. [PMID] 22173708.
2012
Non-viral iPSCs: a safe way for therapy?
. 3(4):241-245
2012
Reprogramming based gene therapy for inherited red blood cell disorders
Cell Research. 22(6):1-4 [DOI] 10.1038/cr.2012.54. [PMID] 22473006.
2011
Tumor infiltrating CD4+ T cells stimulate mammary/breast cancer metastasis through activation of RANKL-RANK signaling
Nature. 470(7335):548-553 [DOI] 10.1038/nature09707. [PMID] 21326202.
2010
B cell activating factor and c-Myc regulate progression of B cell chronic lymphocytic leukemia
Proceedings of the National Academy of Sciences. 107(44):18956-18960 [DOI] 10.1073/pnas.1013420107. [PMID] 20956327.
2010
Magnetically Vectored Nanocapsules for Tumor Penetration and Remotely Switchable On-Demand Drug Release
Nano Letters. 10(12):5088-5092 [DOI] 10.1021/nl1033733. [PMID] 21038917.
2009
Chronic lymphocytic leukemia of Emu-TCL1 transgenic mice undergoes rapid cell turnover that can be offset by extrinsic CD257 to accelerate disease progression.
Blood. 114(20):4469-76 [DOI] 10.1182/blood-2009-06-230169. [PMID] 19755673.
2008
Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery
Current Cancer Drug Targets. 8(1):2-6 [PMID] 18288938.
View on: PubMed
2008
Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex
Science. 321(5889):663-668 [DOI] 10.1126/science.1157340. [PMID] 18635759.
2008
RACK1 and CIS mediate the degradation of BimEL in cancer cells
Journal of Biological Chemistry. 283(4):16416-16426 [DOI] 10.1074/jbc.M802360200. [PMID] 18420585.
2008
Regulation of cancer cell survival, migration and invasion by TWIST:AKT2 comes to interplay
Cancer research. 68(4):957-960 [DOI] 10.1158/0008-5472.CAN-07-5067. [PMID] 18281467.
2008
TRAF2 and TRAF3 carry out non-redundant and complementary functions to activate IKK-dependent alternative NF-κB signaling
Nature Immunology. 9(12):1364-1370 [DOI] 10.1038/ni.1678. [PMID] 18997792.
2008
Twist is Transcriptionally Induced by Activation of STAT3 and Mediates STAT3 Oncogenic Function
Journal of Biological Chemistry. 283(21):14665-14673 [DOI] 10.1074/jbc.M707429200. [PMID] 18353781.
2007
Transcriptional profile of Rous Sarcoma Virus transformed chicken embryo fibroblasts reveals new signaling targets of viral-src
Virology. 364(1):10-20 [PMID] 17448517.
View on: PubMed
2007
Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel.
Cancer research. 67(5):1979-87 [PMID] 17332325.
View on: PubMed
2006
RACK1 recruits STAT3 specifically to insulin and insulin-like growth factor 1 receptors for activation, which is important for regulating anchorage-independent growth.
Molecular and cellular biology. 26(2):413-24 [PMID] 16382134.
View on: PubMed
2005
Receptor For Activated C Kinase 1 mediates activation of Jun N-terminal Kinase by Protein Kinase C
Molecular Cell. 19(3):309-320
2004
Amphibacillus haojiensis sp. nov.–A novel Alkaliphilic and Slight Halophilic Bacterium from Haoji Soda Lake in Inner Mongolia Autonomous Region, China
Wei sheng wu xue bao = Acta microbiologica Sinica. 44(6):720-723 [PMID] 16110946.
View on: PubMed
2004
Bacterial diversity of the Inner Mongolian Baer Soda Lake as revealed by 16S rRNA gene sequence analyses.
Extremophiles : life under extreme conditions. 8(1):45-51 [PMID] 15064989.
View on: PubMed
2002
Marinospirillum alkaliphilum sp. nov., a new alkaliphilic helical bacterium from Haoji soda lake in Inner Mongolia Autonomous Region of China.
Extremophiles : life under extreme conditions. 6(1):33-7 [PMID] 11878559.
View on: PubMed
2002
Salinicoccus alkaliphilus sp. nov., a novel alkaliphile and moderate halophile from Baer Soda Lake in Inner Mongolia Autonomous Region, China.
International journal of systematic and evolutionary microbiology. 52(Pt 3):789-793 [DOI] 10.1099/00207713-52-3-789. [PMID] 12054239.
2001
The diversity of alkaliphiles from hailaer soda lake, Inner Mongolia
. 9(1):44-50

Grants

Apr 2021 ACTIVE
Proteolysis-targeting chimera against BCL-XL inhibits breast cancer metastasis
Role: Principal Investigator
Funding: NATL INST OF HLTH NCI
Feb 2021 ACTIVE
Energy Balance, mTOR pathway signaling, and breast cancer prognosis
Role: Co-Investigator
Funding: NATL INST OF HLTH NCI
Jan 2021 ACTIVE
Developing a Novel PROTAC-Based NR4A1 Degrader for Breast Cancer Therapy
Role: Principal Investigator
Funding: US ARMY MED RES ACQUISITION
Dec 2020 ACTIVE
Sanofi 2020 iAwards
Role: Principal Investigator
Funding: SANOFI
Sep 2020 ACTIVE
Integrated transcriptomic profiling of recurrent parotitis in pediatric Sj?grens syndrome for assessment of mitochondrial RNA regulators
Role: Co-Investigator
Funding: SJOGRENS SYNDROME FOU
Apr 2019 ACTIVE
Modulating Cancer Genetics for Immune Regulation and Breast Cancer Therapy
Role: Principal Investigator
Funding: US ARMY MED RES ACQUISITION
Mar 2019 ACTIVE
CD177 suppresses breast-cancer development by inhibiting beta-catenin
Role: Principal Investigator
Funding: NATL INST OF HLTH NCI
Dec 2015 ACTIVE
Obesity, inflammation and breast cancer
Role: Principal Investigator
Funding: NATL INST OF HLTH NCI
Jul 2010 ACTIVE
Dr. and Mrs. James Robert Spencer Professorship of Pathology, Immunology, and Laboratory Medicine
Role: Principal Investigator
Funding: UF FOU

Education

Postdoctoral Fellow
2007-2012 · University of California, San Deigo
Ph.D.
2001-2006 · Mount Sinai School of Medicine, NYU, New York, United States
M.S.
1998-2001 · Institute of Microbiology, CAS, Beijing, China
B.A.
1994-1998 · Nankai University, Tianjin, China

Teaching Profile

Courses Taught
2019-2021
GMS6647 Transcriptional and Translational Control of Cell Growth and Proliferation
2021
GMS6140 Principles of Immunology

Contact Details

Phones:
Business:
(352) 273-6748
Emails:
Business:
zhangw@ufl.edu