Xin Lu John M. and Mary Jo Boler Collegiate 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 investigate both cancer-cell-intrinsic and -extrinsic mechanisms of immune evasion and immunotherapy resistance. Our research has revealed a number of targetable mechanisms on how the oncogenic signaling in neoplastic cells (“cancer-cell-intrinsic”) exerts the cell non-autonomous functions to control the cancer-immune interactome in solid tumors. For example, our publication is Science Immunology (2023) found that cancer cell expression of the chromatin effector Pygo2 promotes immunotherapy resistance by restraining tumor T cell infiltration and cytotoxicity. Another publication on Cell Metabolism (2023) reveal how tumor-infiltrating neutrophils escape from ferroptosis (a newly identified iron-dependent non-apoptosis cell deathh) through the aconitate decarboxylase 1 (Acod1)-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis. To make these findings, we employ diverse types of models and techniques, such as genetically engineered mice and cell models, functional genomics, experimental therapeutics, and cutting-edge experimental and computational methodologies (single cell RNA-seq, spatial transcriptomics, high-throughput drug and CRISPR/cas9 screen, molecular digital pathology, multi-omics integration, etc.).

We are equally interested in the most prevalent cancer types that both women and men suffer from (breast, prostate, pancreas, kidney), 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.

Our research is supported by federal grants, private foundations and institutional funds. We are actively recruiting graduate students, postdoctoral fellows and undergraduate students, who are passionate about transforming cancer medicine to benefit human health and society. Please email Dr. Lu directly if you are interested in joining us!

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:

View all of Xin Lu's Publications with link to PubMed: https://www.ncbi.nlm.nih.gov/myncbi/14A325uGbh1Ab/bibliography/public/

Important Note: Below only shows the papers with Xin Lu as the corresponding author and/or first author since 2016. Lu lab also actively co-publishes works with collaborating chemists, bioengineers and bioinformaticians, so please click the link above to see our full list of publications on PubMed.

• Zhao Y, Liu Z, Liu G, Zhang Y, Liu S, Gan D, Chang W, Peng X, Sung ES, Gilbert K, Zhu Y, Wang X, Zeng Z, Baldwin H, Ren G, Weaver J, Huron A, Mayberry T, Wang Q, Wang Y, Diaz-Rubio ME, Su X, Stack MS, Zhang S, Lu X, Sheldon RD, Li J, Zhang C, Wan J, Lu X. Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. Cell Metabolism. 2023 Oct 3;35(10):1688-1703.e10. doi: 10.1016/j.cmet.2023.09.004. PubMed PMID: 37793345; PubMed Central PMCID: PMC10558089.

• Zhu Y, Zhao Y, Wen J, Liu S, Huang T, Hatial I, Peng X, Al Janabi H, Huang G, Mittlesteadt J, Cheng M, Bhardwaj A, Ashfeld BL, Kao KR, Maeda DY, Dai X, Wiest O, Blagg BSJ, Lu X, Cheng L, Wan J, Lu X. Targeting the chromatin effector Pygo2 promotes cytotoxic T cell responses and overcomes immunotherapy resistance in prostate cancer. Sci Immunol. 2023 Mar 17;8(81):eade4656. doi: 10.1126/sciimmunol.ade4656. Epub 2023 Mar 10. PubMed PMID: 36897957.

• Zhu Y, Duong L, Lu X, Lu X. Cancer-cell-intrinsic mechanisms shaping the immunosuppressive landscape of prostate cancer. Asian J Androl. 2023 Mar-Apr;25(2):171-178. doi: 10.4103/aja202283. Review. PubMed PMID: 36367020.

• Lu X, Liu X, Celià-Terrassa T, Ren G. Editorial: Stromal and immune microenvironment in breast cancer metastasis. Front Immunol. 2022;13:1104362. doi: 10.3389/fimmu.2022.1104362. eCollection 2022. PubMed PMID: 36561756; PubMed Central PMCID: PMC9763918.

• Rahmy S, Mishra SJ, Murphy S, Blagg BSJ, Lu X. Hsp90β inhibition upregulates interferon response and enhances immune checkpoint blockade therapy in murine tumors. Front Immunol. 2022;13:1005045. doi: 10.3389/fimmu.2022.1005045. eCollection 2022. PubMed PMID: 36341371; PubMed Central PMCID: PMC9630337.

• Lu X, Lu X. Enhancing immune checkpoint blockade therapy of genitourinary malignancies by co-targeting PMN-MDSCs. Biochim Biophys Acta Rev Cancer. 2022 May;1877(3):188702. doi: 10.1016/j.bbcan.2022.188702. Epub 2022 Feb 25. PubMed PMID: 35227829; PubMed Central PMCID: PMC9177662.

• Wang X, Hu J, Fang Y, Fu Y, Liu B, Zhang C, Feng S, Lu X. Multi-Omics Profiling to Assess Signaling Changes upon VHL Restoration and Identify Putative VHL Substrates in Clear Cell Renal Cell Carcinoma Cell Lines. Cells. 2022 Jan 29;11(3). doi: 10.3390/cells11030472. PubMed PMID: 35159281; PubMed Central PMCID: PMC8833913.

• 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.

• Zhu Y, Wen J, Huang G, Mittlesteadt J, Wen X, Lu X. CHD1 and SPOP synergistically protect prostate epithelial cells from DNA damage. Prostate. 2021 Jan;81(1):81-88. doi: 10.1002/pros.24080. Epub 2020 Oct 6. PubMed PMID: 33022763.

• 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.

• 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.

• 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.

• 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 Jul;6(3):171-177. doi: 10.1002/cjp2.160. Epub 2020 Mar 9. PubMed PMID: 32149481; PubMed Central PMCID: PMC7339199.

• 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.

• 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.

• 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; PubMed Central PMCID: PMC7178187.

• 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; PubMed Central PMCID: PMC7045488.

• Zhang Y, Guoqiang L, Sun M, Lu X. Targeting and exploitation of tumor-associated neutrophils to enhance immunotherapy and drug delivery for cancer treatment. Cancer Biol Med. 2020 Feb 15;17(1):32-43. doi: 10.20892/j.issn.2095-3941.2019.0372. Review. PubMed PMID: 32296575; PubMed Central PMCID: PMC7142839.

• 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.

• 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 U S A. 2018 Oct 2;115(40):10094-10099. doi: 10.1073/pnas.1800695115. Epub 2018 Sep 19. PubMed PMID: 30232256; PubMed Central PMCID: PMC6176562.

• 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 Res. 2018 Jul 15;78(14):3823-3833. doi: 10.1158/0008-5472.CAN-17-3564. Epub 2018 May 16. PubMed PMID: 29769196; PubMed Central PMCID: PMC6381393.

• Lu X, Jin EJ, Cheng X, Feng S, Shang X, Deng P, Jiang S, Chang Q, Rahmy S, Chaudhary S, Lu X, Zhao R, Wang YA, DePinho RA. Opposing roles of TGFβ and BMP signaling in prostate cancer development. Genes Dev. 2017 Dec 1;31(23-24):2337-2342. doi: 10.1101/gad.307116.117. PubMed PMID: 29352019; PubMed Central PMCID: PMC5795781.

• Lu X, Horner JW, Paul E, Shang X, Troncoso P, Deng P, Jiang S, Chang Q, Spring DJ, Sharma P, Zebala JA, Maeda DY, Wang YA, DePinho RA. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature. 2017 Mar 30;543(7647):728-732. doi: 10.1038/nature21676. Epub 2017 Mar 20. PubMed PMID: 28321130; PubMed Central PMCID: PMC5374023.

• Wang G, Lu X, Dey P, Deng P, Wu CC, Jiang S, Fang Z, Zhao K, Konaparthi R, Hua S, Zhang J, Li-Ning-Tapia EM, Kapoor A, Wu CJ, Patel NB, Guo Z, Ramamoorthy V, Tieu TN, Heffernan T, Zhao D, Shang X, Khadka S, Hou P, Hu B, Jin EJ, Yao W, Pan X, Ding Z, Shi Y, Li L, Chang Q, Troncoso P, Logothetis CJ, McArthur MJ, Chin L, Wang YA, DePinho RA. Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression. Cancer Discov. 2016 Jan;6(1):80-95. doi: 10.1158/2159-8290.CD-15-0224. PubMed PMID: 26701088; PubMed Central PMCID: PMC4707102.