Xin Lu John M. and Mary Jo Boler Associate Professor

Research Interests:

Understanding and targeting the tumor microenvironment is at the forefront of current basic and translational cancer research. Targeting tumor microenvironment is closely related to tumor immunology and immunotherapy, one of the most exciting and rapidly evolving areas of cancer research. An intense focus of research in our lab is to investigate the molecular and cellular mechanisms underlying the cancer ─ tumor microenvironment crosstalk, in particular interactions between cancer cells and the myeloid compartment, in both primary tumors and metastases to bone and other organs. We propose that the efficacy of immune checkpoint blockade drugs (e.g. anti-CTLA4, anti-PD1 antibodies) on refractory metastatic cancer can be potently enhanced when combined with other therapy modalities, including targeted therapy that specifically antagonize immunosuppressive activities yet preserve T cell functions in the tumor microenvironment. Recent publications from the Lu lab firmly establish that immunosuppressive neutrophils (also known as polymorphonuclear myeloid-derived suppressor cells, PMN-MDSCs), play the predominant role in inducing the exhaustion of effector T cells in the tumor microenvironment across multiple solid tumors. A number of mechanisms and targeting strategies of PMN-MDSCs have been reported by the Lu lab including the CXCR1/2 inhibitor SX-682, the tyrosine kinase inhibitor cabozantinib, and the cyclooxygenase-2 inhibitor celecoxib, which may open new avenues to sensitize advanced malignancies to immune checkpoint blockade therapy. Dr. Lu also investigates and develops novel immuno-therapeutics and molecularly-targeted therapeutics, including antibody-drug conjugates, chimeric antigen receptor (CAR)-engineered NK cells and small molecules targeting transcription coactivators that promote metastasis. Through creating new models of immunosuppressive neutrophils and animal models with key genes knocked-out in neutrophils, we are on the path to identify more specific and potent therapeutic strategies on the “bad” immune compartment of solid tumors.

We are equally interested in the most prevalent cancer types both men and women suffer from (prostate cancer and breast cancer), as well as rare cancer types such as penile cancer and Von Hippel-Lindau disease (VHL). As part of the Center for Rare and Neglected Diseases (CRND), our mission is to understand and eliminate cancer in the near future through bench-to-bedside translational research and partnership with drug discovery powerhouses. To achieve our research goals, we integrate a diverse array of cutting-edge approaches, such as CRISPR-engineered mouse models, functional genomics, bioinformatics experimental therapeutics, CRISPR/cas9 genome editing, single cell RNA-seq, CyTOF, high-throughput drug screening, molecular digital pathology, and so on.

We are constantly seeking new lab members including graduate students, postdoctoral fellows and undergraduate students, who are passionate about transforming cancer medicine to benefit human health and society. 

Biography:

• John M. and Mary Jo Boler Associate Professor, Department of Biological Sciences, University of Notre Dame, IN 2022-Present
• John M. and Mary Jo Boler Assistant Professor, Department of Biological Sciences, University of Notre Dame, IN 2017-2022
• Junior Chair, Boler-Parseghian Center for Rare and Neglected Diseases; Full member, Harper Cancer Research Institute (HCRI); Cluster Chair, Cellular & Molecular Biology Cluster, Integrated Biomedical Sciences (IBMS) PhD Program; Member, Chemistry-Biochemistry-Biology Interface (CBBI) Program; Member, Warren Family Center for Drug Discovery; Member, Eck Institute for Global Health (EIGH); Member, Advanced Diagnostics & Therapeutics (AD&T), University of Notre Dame
• Full Member, Tumor Microenvironment and Metastasis Program, Indiana University Melvin and Bren Simon Cancer Center (NCI-designated comprehensive cancer center)
• Instructor, Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 2014-2016
• Jane Coffin Childs Postdoctoral Fellow. Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 2011-2014  (Mentor: Ronald A. DePinho)
• Jane Coffin Childs Postdoctoral Fellow. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 2010-2011 (Mentor: Ronald A. DePinho)
• Ph.D. (Molecular Biology), Princeton University, Princeton, NJ 2004-2010  (Mentor: Yibin Kang)
• B.S. (Biological Sciences), Tsinghua University, Beijing, China 2000-2004

Recent Papers:

• Zhao Y, Peng X, Baldwin H, Zhang C, Liu Z, Lu X. Anti-androgen therapy induces transcriptomic reprogramming in metastatic castration-resistant prostate cancer in a murine model. Biochim Biophys Acta Mol Basis Dis. 2021 Jul 1;1867(7):166151. doi: 10.1016/j.bbadis.2021.166151. Epub 2021 Apr 21. PubMed PMID: 33892077.
• Chahoud J, Gleber-Netto FO, McCormick BZ, Rao P, Lu X, Guo M, Morgan MB, Chu RA, Martinez-Ferrer M, Eterovic AK, Pickering CR, Pettaway CA. Whole Exome Sequencing in Penile Squamous Cell Carcinoma Uncovers Novel Prognostic Categorization and Drug Targets Similar to Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. 2021 May 1;27(9):2560-2570. doi: 10.1158/1078-0432.CCR-20-4004. Epub 2021 Jan 13. PubMed PMID: 33441293.
• Shen M, Xie S, Rowicki M, Michel S, Wei Y, Hang X, Wan L, Lu X, Yuan M, Jin JF, Jaschinski F, Zhou T, Klar R, Kang Y. Therapeutic Targeting of Metadherin Suppresses Colorectal and Lung Cancer Progression and Metastasis. Cancer Res. 2020 Nov 25;. doi: 10.1158/0008-5472.CAN-20-1876. [Epub ahead of print] PubMed PMID: 33239430.
• Zhang Y, Wilt E, Lu X. Human Isogenic Cell Line Models for Neutrophils and Myeloid-Derived Suppressor Cells. Int J Mol Sci. 2020 Oct 18;21(20). doi: 10.3390/ijms21207709. PubMed PMID: 33081041; PubMed Central PMCID: PMC7590135.
• Zhu Y, Wen J, Huang G, Mittlesteadt J, Wen X, Lu X. CHD1 and SPOP synergistically protect prostate epithelial cells from DNA damage. Prostate. 2020 Oct 6;. doi: 10.1002/pros.24080. [Epub ahead of print] PubMed PMID: 33022763.
• Luo Y, Medina Bengtsson L, Wang X, Huang T, Liu G, Murphy S, Wang C, Koren J 3rd, Schafer Z, Lu X. UQCRH downregulation promotes Warburg effect in renal cell carcinoma cells. Sci Rep. 2020 Sep 14;10(1):15021. doi: 10.1038/s41598-020-72107-2. PubMed PMID: 32929120; PubMed Central PMCID: PMC7490363.
• Huang T, Cheng X, Chahoud J, Sarhan A, Tamboli P, Rao P, Guo M, Manyam G, Zhang L, Xiang Y, Han L, Shang X, Deng P, Luo Y, Lu X, Feng S, Ferrer MM, Alan Wang Y, DePinho RA, Pettaway CA, Lu X. Effective combinatorial immunotherapy for penile squamous cell carcinoma. Nat Commun. 2020 May 1;11(1):2124. doi: 10.1038/s41467-020-15980-9. PubMed PMID: 32358507; PubMed Central PMCID: PMC7195486.
• Zhao Y, Rahmy S, Liu Z, Zhang C, Lu X. Rational targeting of immunosuppressive neutrophils in cancer. Pharmacol Ther. 2020 Aug;212:107556. doi: 10.1016/j.pharmthera.2020.107556. Epub 2020 Apr 25. Review. PubMed PMID: 32343986.
• Zhao D, Cai L, Lu X, Liang X, Li J, Chen P, Ittmann M, Shang X, Jiang S, Li H, Meng C, Flores I, Song JH, Horner JW, Lan Z, Wu CJ, Li J, Chang Q, Chen KC, Wang G, Deng P, Spring DJ, Wang YA, DePinho RA. Chromatin Regulator, CHD1, Remodels the Immunosuppressive Tumor Microenvironment in PTEN-Deficient Prostate Cancer. Cancer Discov. 2020 May 8;. doi: 10.1158/2159-8290.CD-19-1352. [Epub ahead of print] PubMed PMID: 32385075.
• Zhang Y*, Liu G*, Sun M*, Lu X. Targeting and Exploiting Tumor-associated Neutrophils to Enhance Immunotherapy and Drug Delivery for Cancer Treatment. Cancer Biology & Medicine. 2020; 17: 32-43. doi: 10.20892/j.issn.2095-3941.2019.0372.
• Rahmy S, Cheng X, Wang M, Feng H, Qiu W, Zhao R, Lu X. Organ-specific regulation of CHD1 by acute PTEN and p53 loss in mice. Biochem Biophys Res Commun. 2020 May 7;525(3):614-619. doi: 10.1016/j.bbrc.2020.02.136. Epub 2020 Feb 27. PubMed PMID: 32115152.
• Liu G, Jin Z, Lu X. Differential Targeting of Gr-MDSCs, T Cells and Prostate Cancer Cells by Dactolisib and Dasatinib. Int J Mol Sci. 2020 Mar 27;21(7). doi: 10.3390/ijms21072337. PubMed PMID: 32230980.
• Wen J, Huang G, Liu S, Wan J, Wang X, Zhu Y, Kaliney W, Zhang C, Cheng L, Wen X, Lu X. Polymorphonuclear MDSCs are enriched in the stroma and expanded in metastases of prostate cancer. J Pathol Clin Res. 2020 Mar 9;. doi: 10.1002/cjp2.160. [Epub ahead of print] PubMed PMID: 32149481.
• Song J, Park S, Oh J, Kim D, Ryu JH, Park WC, Baek IJ, Cheng X, Lu X, Jin EJ. NUDT7 Loss Promotes KrasG12D CRC Development. Cancers (Basel). 2020 Mar 2;12(3). doi: 10.3390/cancers12030576. PubMed PMID: 32131398.
• Liu F, Calhoun B, Alam MS, Sun M, Wang X, Zhang C, Haldar K, Lu X. Case report: a synonymous VHL mutation (c.414A > G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing. BMC Med Genet. 2020 Feb 27;21(1):42. doi: 10.1186/s12881-020-0976-7. PubMed PMID: 32106822
• Wang Q, Guldner IH, Golomb SM, Sun L, Harris JA, Lu X, Zhang S. Single-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4/6 inhibitor-resistant HER2-positive breast cancer. Nat Commun. 2019 Aug 23;10(1):3817. doi: 10.1038/s41467-019-11729-1. PubMed PMID: 31444334; PubMed Central PMCID: PMC6707314.
• Cheng X, Jin Z, Ji X, Shen X, Feng H, Morgenlander W, Ou B, Wu H, Gao H, Ye F, Zhang Y, Peng Y, Liang J, Jiang Y, Zhang T, Qiu W, Lu X#, Zhao R#. ETS variant 5 promotes colorectal cancer angiogenesis by targeting platelet-derived growth factor BB. Int J Cancer. 2019 Jul 1;145(1):179-191. doi: 10.1002/ijc.32071. Epub 2019 Jan 28. PubMed PMID: 30650178.
• Feng S, Wen X, Lu X#. Nitropeptide Profiling and Identification Illustrated by Angiotensin II. J Vis Exp. 2019 Jun 16;(148). doi: 10.3791/59391. PubMed PMID: 31259896.
• Zhang L, Shen H, Gong Y, Pang X, Yi M, Guo L, Li J, Arroyo S, Lu X, Ovchinnikov S, Cheng G, Liu X, Jiang X, Feng S, Deng H. Development of a dual-functional conjugate of antigenic peptide and Fc-III mimetics (DCAF) for targeted antibody blocking. Chem Sci. 2019 Mar 21;10(11):3271-3280. doi: 10.1039/c8sc05273e. eCollection 2019 Mar 21. PubMed PMID: 30996912; PubMed Central PMCID: PMC6429600.
• Feng S, Cheng X, Zhang L, Lu X, Chaudhary S, Teng R, Frederickson C, Champion MM, Zhao R, Cheng L, Gong Y, Deng H, Lu X. Myeloid-Derived Suppressor Cells Inhibit T Cell Activation through Nitrating LCK in Mouse Cancers. Proc. Natl. Acad. Sci., 2018; 115(40):10094-10099. [PMID: 30232256]
• Lu X*, Pan X*, Wu CJ, Zhao D, Feng S, Zang Y, Lee R, Khadka S, Amin SB, Jin EJ, Shang X, Deng P, Luo Y, Morgenlander WR, Weinrich J, Lu X, Jiang S, Chang Q, Navone NM, Troncoso P, DePinho RA, Wang YA. An In Vivo Screen Identifies PYGO2 as a Driver for Metastatic Prostate Cancer. Cancer Research. 2018; 78(14):3823-3833. [PMID: 29769196]
• Lu X, Jin E, Cheng X, Feng S, Shang X, Deng P, Jiang S, Chang Q, Rahmy S, Chaudhary S, Lu Xuemin, Wang YA, DePinho RA. Opposing Roles of TGFβ and BMP Signaling in Prostate Cancer Development. Genes & Development. 2017; 31(23-24):2337-2342.  
• Lu X, Horner JW, Paul E, Shang X, Troncoso P, Deng P, Jiang S, Chang Q, Varma A, Han JW, Spring DJ, Sharma P, Zebala JA, Maeda DY, Wang YA, and DePinho RA. Effective Combinatorial Immunotherapy for Metastatic Castration-Resistant Prostate Cancer. Nature. 2017; 543:728-732.
• Zhao D, Lu X, Wang G, Lan Z, Liao W, Li J, Liang X, Chen JR, Shah S, Shang X, Tang M, Deng P, Dey P, Chakravarti D, Chen P, Spring DJ, Navone NM, Troncoso P, Zhang J, Wang YA, DePinho RA. Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer. Nature. 2017;542:484-488.
• Hu B, Wang Q, Wang YA, Hua S, Sauvé CG, Ong D, Lan ZD, Chang Q, Ho YW, Monasterio MM, Lu X, Zhong Y, Zhang J, Deng P, Tan Z, Wang G, Liao WT, Corley LJ, Yan H, Zhang J, You Y, Liu N, Cai L, Finocchiaro G, Phillips JJ, Berger MS, Spring DJ, Hu J, Sulman EP, Fuller GN, Chin L, Verhaak RG, DePinho RA. Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth. Cell. 2016; 167(5):1281-1295
• Wang G*, Lu X*, Dey P, Deng P, Wu C, Jiang S, Fang Z, Zhao K, Konaparthi R, Hua S, Zhang J, Tapia E,Kapoor A, Wu C, Patel N, Guo Z, Ramamoorthy V, Tieu T, Heffernan T, Zhao D, Shang X, Khadka S, Hou P, Hu B, Jin E, Yao W, Pan X, Ding Z, Shi Y, Li L, Chang Q, Troncoso P, Logothetis C, McArthur M, Chin L, Wang YA, DePinho RA. Targeting YAP-dependent MDSC infiltration impairs tumor progression. Cancer Discovery. 2016 Jan;6(1):80-95. (*Co-first authors with equal contribution)
• Wan L, Lu X, Yuan S, Wei Y, Guo F, Shen M, Yuan M, Chakrabarti R, Hua Y, Smith HA, Blanco MA, Chekmareva M, Wu H, Bronson RT, Haffty BG, Xin Y, Kang Y. MTDH-SND1 Interaction Is Crucial for Expansion and Activity of Tumor-Initiating Cells in Diverse Oncogene- and Carcinogen-Induced Mammary Tumors. Cancer Cell. 2014: 26(1):92-105
• Lu X*, Agasti S*, Vinegoni C, Waterman P, DePinho RA, Weissleder R. Optochemogenetics (OCG) allows more precise control of genetic engineering in mice with CreER regulators. Bioconjugate Chemistry. 2012: 23(9):1945-51. (*Co-first author)
• Ding Z, Wu CJ, Jaskelioff M, Ivanova E, Kost-Alimova M, Protopopov A, Chu GC, Wang G, Lu X, Labrot ES, Hu J, Wang W, Xiao Y, Zhang H, Zhang J, Zhang J, Gan B, Perry SR, Jiang S, Li L, Horner JW, Wang YA, Chin L, DePinho RA. Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases. Cell. 2012; 148:896-907.
• Lu X, Mu E, Wei Y, Riethdorf S, Yang Q, Yuan M, Yan J, Hua Y, Tiede B, Lu X, Haffty B, Pantel K, Massagué J, and Kang Y. VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging α4β1-positive osteoclast progenitors. Cancer Cell. 2011; 20:701-714. (Featured Article)