Description of Research Expertise

Research Interests

1) Investigate the critical role and underlying mechanism for the tumor suppressor, Menin, in epigenetic regulation of gene transcription, beta cell signaling and proliferation, neuroendocrine tumors (NETs), colorectal cancer (CRC), and acute myeloid leukemia (AML).
2) Identify immunologically targetable tumor-associating antigens (TAAs) of NETs and AML and their respective nanobodies.
3) Develop novel chimeric antigen receptor (CAR)-expressing T cells (CART), including bispecific CAR T, to target NETs, CRC, and AML to improve immunotherapy.
4) Investigate how inhibition of Menin by small molecule inhibitors influences beta cell proliferation and dysregulation of metabolism in colorectal cancer (CRC) cells.

Key words: Menin, beta cells, epigenetics, neuroendocrine tumors (NETs), acute myeloid leukemia (AML), chimeric antigen receptor (CAR) T cells, colorectal cancer (CRC), immunotherapy.

Description of Research

Our research focuses on elucidating the molecular mechanisms whereby Menin, a contextual tumor suppressor and scaffold protein that interacts with multiple epigenetic regulators, in regulating normal cells and cancers. We seek to investigate how the Menin pathway regulates pancreatic beta cells, neuroendocrine tumors (NETs), colorectal cancer (CRC), and a subset of acute myeloid leukemia (AML). Moreover, we have invented Sequential Tumor-selected Antibody and antigen-Retrieval (STAR) platform to isolate NET and AML-selective nanobodies, and are developing novel and effective Chimeric Antigen Receptor (CAR) T cells to treat NETs and AML. We use a wide range of approaches including protein and cell engineering, synthetic biology, bioinformatics, gene editing, immunology, and immunotherapy in our investigation.

1. We seek to elucidate how menin controls pancreatic beta cells via regulation of menin phosphorylation and gene transcription, histone methylations, and expression of pro-proliferative genes. This allows us to analyze how the menin-modulated key pathways influence menin regulated neuroendocrine tumors and AML.

2. Develop novel CAR T therapy to target neuroendocrine tumors (NETs) and colorectal cancer (CRC), and improve the CAR T cell’s ability to withstand suppressive tumor microenvironment (TME) using multi-pronged approaches.

3. Develop novel bispecific and split CAR (CD13/TIM-3 CAR) T cells targeting AML to increase specificity and reduce toxicity, thereby improving AML immunotherapy.

4. Investigate how inhibition of menin by small molecule inhibitors leads to increased beta cell proliferation and reversal of diabetes, as well as dysregulation of metabolism including glycolysis in colorectal cancer (CRC) cells.

These comprehensive approaches will provide novel insights into the molecular mechanisms of menin-mediated epigenetic regulation of beta cells, NETs, AML, and CRC, thereby paving the way to developing novel and more effective immunotherapy for AML and the solid tumors.

Rotation Projects
1. Investigate how menin and its epigenetic partners control gene transcription and how the control system is dysregulated in neuroendocrine tumors.
2. Identify the antigens of nanobodies specifically targeting NETs or AML.
3. Develop enhanced CAR T cells that are resistant to suppressive tumor microenvironments.
4. Develop conditionally inducible CAR T cells to suppress NETs or AML.

Lab personnel:
Heather Birmingham, Administrative Assistant (hbir@upenn.edu)
Alison Knowles, Research Specialist and Lab Manager
Zijie Feng, Postdoctoral Researcher
Taylor Hojnacki, Research Specialist
Xin He, Research Associate
Bryson Katona, Gastroenterologist
Yan Cao, Visiting Student
Jian Ma, Postdoctoral Researcher
Bowen Xing, Postdoctoral Researcher
Xuyao Zhang, Postdoctoral Researcher

Selected Publications

Thiel, A.T., Blessington, P., Zou, T., Feather, D, Wu, X., Zhang, H., Liu, L., Koretzky, G., Ernst, P., and Hua, X: MLL-AF9-induced leukemic transformation requires co-expression of wild type MLL allele Cancer Cell 17 (2): 148-159,2010.

Jing Huang, Buddha Gurung, Bingbing Wan, Smita Matkar, Natalia A. Veniaminova, Ke Wan, Juanita L. Merchant, Xianxin Hua*, and Ming Lei* (*co-corresponding author): The same pocket in menin binds both MLL and JunD, but oppositely regulates transcription Nature 432 (7386): 542-6,2012.

Matkar S, Sharma P, Gao S, Gurung B, Katona BW, Liao J, Muhammad AB, Kong XC, Wang L, Jin G, Dang CV, Hua X: An Epigenetic Pathway Regulates Sensitivity of Breast Cancer Cells to HER2 Inhibition via FOXO/c-Myc Axis Cancer Cell 28 (4): 472-85,2015.

Zhu J, Sammons MA, Donahue G, Dou Z, Vedadi M, Getlik M, Barsyte-Lovejoy D, Al-awar R, Katona BW, Shilatifard A, Huang J, Hua X, Arrowsmith CH, Berger SL: Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth Nature 525 (7568): 206-11,2015.

Zijie Feng, Lei Wang, Yanmei Sun, Zongzhe Jiang, Bowen Xing, John Domsic, Jingjing Tian, David C. Metz, Xiaolu Yang, Ronen Marmostein, Xiaosong Ma and Xianxin Hua: Menin and Daxx Interact to Control Pancreatic Neuroendocrine Tumors via Epigenetic Regulation of Membrane Metallo-Endopeptidase Cancer Research 77 (2): 401-411,2017.

Katona BW, Glynn RA, Paulosky KE, Feng Z, Davis CI, Ma J, Berry CT, Szigety KM, Matkar S, Liu Y, Wang H, Wu Y, He X, Freedman BD, Brady DC, Hua X: Combined Menin and EGFR Inhibitors Synergize to Suppress Colorectal Cancer via EGFR-Independent and Calcium-Mediated Repression of SKP2 Transcription Cancer Research 79 (9): 2195-2207,2019.

Wu Y, Doepner M, Hojnacki T, Feng Z, Katona BW, He X, Ma J, Cao Y, Busino L, Zhou F, Hua X: Disruption of the menin-MLL interaction triggers menin protein degradation via ubiquitin-proteasome pathway Am. J. Cancer Res 9 (8): 1682-1694,2019.

Ma J, He X, Cao Y, O’Dwyer K, Szigety KM, Wu Y, Gurung B, Feng Z, Katona BW, Hua X: Islet-specific Prmt5 excision leads to reduced insulin expression and glucose intolerance in mice J. Endocrinol. 244 (1): 41-52,2020.

He X, Feng Z, Ma J, Ling S, Cao Y, Gurung B, Wu Y, Katona BW, O'Dwyer KP, Siegel DL, June CH, Hua X.: Bispecific and split CAR T cells targeting CD13 and TIM3 eradicate acute myeloid leukemia. Blood 135 (10): 713-723,2020.

Zijie Feng, Xin He, Xuyao Zhang, Yuan Wu, Bowen Xing, Alison Knowles, Qiaonan Shan, Samuel Miller, Taylor Hojnacki, Jian Ma, Bryson W. Katona, Terence P. F. Gade, Jörg Schrader, David C. Metz, Carl H. June & Xianxin Hua: Potent suppression of neuroendocrine tumors and gastrointestinal cancers by CDH17CAR T cells without toxicity to normal tissues Nature Cancer : 2022.

Jian Ma1, Bowen Xing, Yan Cao, Xin He, Kate E Bennett, Chao Tong, Chiying An, Taylor Hojnacki, Zijie Feng, Sunbin Deng, Sunbin Ling, Gengchen Xie, Yuan Wu, Yue Ren, Ming Yu, Bryson W Katona, Hongzhe Li, Ali Naji, Xianxin Hua.: Menin-regulated Pbk controls High fat diet-induced compensatory beta cell proliferation. Embo Molecular Medicine 13 (5): 2021.

Xin He, Zijie Feng, Jian Ma, Yan Cao, Sunbin Ling, Xuyao Zhang, Bowen Xing, Bryson W Katona, Carl H June, Xianxin Hua.: CAR T cells targeting CD13 controllably induce eradication of acute myeloid leukemia with a single domain antibody-switch. Leukemia : 2021.

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