Skip to main content

Zhang Lab

Dr. Xinna Zhang’s laboratory has been engaged in basic and translational cancer research in the field of cancer genomics, targeted cancer therapy and immunotherapy. The lab's current study is focused on (1) Identification of new therapeutic targets that drive immune evasion in triple negative breast cancer. (2) Identification of epigenetic inhibitors that enhance tumor antigen presentation using patient-derived organoids.

Research Overview

Triple negative breast cancer (TNBC) are highly aggressive, metastatic, and with the worst prognosis among all types of breast cancers, but no targeted therapy is now available for TNBC. Cancer immunotherapy, notably immune-checkpoint blockade, has shown promise in treating patients with TNBC, but the response rates are up to 10% in unselected TNBC patients and only improves slightly even when patients are selected based on the tumor positivity of PD-L1. There is unmet need to understand potential mechanisms for immune evasion in TNBC. 

Anti-tumor immune responses require functional presentation of tumor antigens and a microenvironment that favors competent immune effectors. Increased antigen presentation on tumor cells can be of therapeutic significance since it makes tumor cells more susceptible to the cytotoxic T lymphocytes. In the preliminary study, we identified a membrane protein, MAL2, as an important player that determines the turnover of the antigen-MHC-I complex and reduces the antigen presentation on breast cancer cells. In preclinical models, inhibition of MAL2 profoundly enhanced the cytotoxicity of tumor-infiltrating CD8+ T cells and suppressed breast tumor growth. This part of work was published in Journal of Clinical Investigation in 2021 and was selected as the cover story recently. 

Epigenetic modification of MHC-I has been observed in a range of cancers and has recently been identified as a mechanism of resistance to immunotherapy. To identify epigenetic inhibitors that enhance tumor antigen presentation and potentiate T cell-mediated cytotoxicity in TNBC, we developed a high-throughput screen approach based on the functional interaction of cytotoxic T cells with 3D breast tumor organoids that resemble the histology of the original tumors. Several epigenetic inhibitors have been identified from the screen and their anti-tumor activities were validated by in vivo tumor models. Part of the work was published in Nature BME in 2021.

Current Research Funding

DoD, PC190042
Identification of Therapeutic Vulnerability in Prostate Cancer Harboring Chromosome 17p Loss

CTSI Showalter Fund
Identification of Epigenetic Inhibitors for Sensitizing TNBC to Immunotherapy

Recent Publications

Zhou Z, Van der Jeught K, Fang Y, Yu T, Li Y, Ao Z, Liu S, Zhang L, Yang Y, Eyvani H, Cox ML, He X, Ji G, Schneider BP, Guo F, Wan J, Zhang X, Lu X (2021). Targeted breast cancer immunotherapy with epigenetic modification of antigen presentation on tumor cells. Nature Biomedical Engineering, 5:1320-1335. (co-corresponding author)

Fang Y, Wang L, Wan C, Sun Y, Van der Jeught K, Zhou Z, Dong T, So KM, Yu T, Li Y, Eyvani H, Colter AB, Dong E, Cao S, Wang J, Schneider BP, Sandusky GE, Liu Y, Zhang C, Lu X, Zhang X (2021). MAL2 drives immune evasion in breast cancer by suppressing tumor antigen presentation, Journal of Clinical Investigation, 2021, 131: e140837. PMID: 32990678. (Corresponding author and the paper was selected as the cover story)

Li Y, Sun Y, Kulke M, Hechler T, Van der Jeught K, Dong T, He B, Miller KD, Radovich M, Schneider BP, Pahl A, Zhang X, Lu X (2021). Targeted immunotherapy for HER2-low breast cancer with 17p loss. Science Translational Medicine. 13: eabc6894. (co-corresponding author)

Liu Y, Xu J, Choi HH, Han C, Fang Y, Li Y, Van der Jeught K, Xu H, Lu Zhang, Frieden M, Wang L, Eyvani H, Sun Y, Zhao G, Zhang Y, Liu S, Wan J, Huang C, Ji G, Lu X, He X, Zhang X (2018). Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast cancer. Nature Communications, 2018, 9: 4718. (Corresponding author)

Li Y, Liu Y, Xu H, Jiang G, Van der Jeught K, Fang Y, Zhou Z, Zhang L, Frieden M, Wang L, Luo Z, Radovich M, Schneider BP, Deng Y, Liu Y, Huang K, He B, Wang J, He X, Zhang X, Ji G, Lu X (2018). Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II, Nature Communications, 9: 4393. (Co-corresponding author)

Pichler M, Stiegelbauer V, Vychytilova-Faltejskova P, Ivan C, Ling H, Winter E, Zhang X, Goblirsch M, Wulf-Goldenberg A, Ohtsuka M, Haybaeck J, Svoboda M, Gerger A, Okugawa Y, Hoefler G, Ajay A, Slaby O, Calin GA (2017). Genome-wide microRNA analysis identifies miR-188-3p as novel prognostic marker and molecular factor involved in colorectal carcinogenesis. Clin Cancer Res, 23:1323-33.

Kanlikilicer P, Rashed MH, Bayraktar R, Mitra R, Ivan C, Aslan B, Zhang X, Filant J, Silva AM, Rodriguez-Aguayo C, Bayraktar E, Pichler M, Ozpolat B, Calin GA, Sood AK, Lopez-Berestein G (2016). Ubiquitous Release of Exosomal Tumor Suppressor miR-6126 from Ovarian Cancer Cells. Cancer Res, 76:7194-207.

Han C, Yang L, Choi H, Baddou J, Achreja A, Liu Y, Li Y, Li J, Wan G, Huang C, Ji G, Zhang X, Nagrath D, Lu X (2016). Amplification of USP13 drives ovarian cancer metabolism. Nat Commun, 7:13525.

Zhang X*, Lopez-Berestein G, Sood AK, Calin GA (2016). Profiling long non-coding RNA expression using custom-designed microarray. Methods Mol Biol, 1402: 33-41 (*corresponding author).

Liu Y, Zhang X, Han C, Wan G, Huang X, Ivan C, Jiang D, Rodriguez-Aguayo C, Lopez-Berestein G, Rao PH, Maru DM, Pahl A, He X, Sood AK, Ellis LM, Anderl J, Lu X(2015). TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature, 520(7549):697-701.

Challagundla KB, Wise PM, Neviani P, Chava H, Murtadha M, Xu T, Kennedy R, Ivan C, Zhang X, Vannini I, Fanini F, Amadori D, Calin GA, Hadjidaniel M, Shimada H, Jong A, Seeger RC, Asgharzadeh S, Goldkorn A, Fabbri M (2015). Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy. J Natl Cancer Inst, 107(7).

Han C, Liu Y, Wan G, Choi HJ, Zhao L, Ivan C, He X, Sood AK, Zhang X*, Lu X (2014). The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression. Cell Rep 8:1447-60 (*co-corresponding author).

Wan G, Zhang X, Langley RR, Liu Y, Hu X, Han C, Peng G, Ellis LM, Jones SN, Lu X (2013). DNA-damage-induced nuclear export of precursor microRNAs is regulated by the ATM-AKT pathway. Cell Rep 3(6):2100-12.

Setoyama T, Zhang X, Natsugoe S, Calin GA (2011). MicroRNA-10b – a new marker or the marker of pancreatic ductal adenocarcinoma. Clin Cancer Re, 17(17):5527-9.

Zhang X, Berger FG, Yang J, Lu X (2011). USP4 inhibits p53 through deubiquitinating and Stabilizing ARF-BP1. EMBO J, 30(11):2177-89.

Research Team

Xinna Zhang, PhD

Assistant Professor of Medical & Molecular Genetics

portrait of Yuanzhang Fang, PhD in the lab

Yuanzhang Fang, PhD

portrait of haniyeh eyvani

Haniyeh Eyvani

Graduate Student