Xin Lu, Ph.D.
My main research goal is to develop novel insights into the genomic, genetic and molecular mechanisms of tumor immunology, organotropic metastasis and treatment resistance, and apply such knowledge to develop and improve therapeutic intervention to benefit cancer patients. I have over 14 years of productive career in cancer research, and my research works have been published in high impact journals (Nature, Cancer Cell, Nature Medicine, Cancer Discovery, PNAS, Cancer Research, Genes & Development, Cell Research, etc.) and recognized by numerous awards. My recent research is centered on mechanistic understanding of myeloid-derived suppressor cells (MDSCs) and developing strategies on targeting MDSCs to enhance immunotherapy. Most recently, I developed an efficient preclinical platform to test combinatorial immunotherapy for metastatic castration-resistant prostate cancer (CRPC) and discovered that inactivating MDSCs with multikinase inhibitors can exert dramatic synergistic efficacy in treating this deadly disease when combined with immune checkpoint blockade (Lu et al. Nature, 2017). My independent research laboratory at University of Notre Dame is focused on identifying cancer cell intrinsic and extrinsic mechanisms of tumor escape of immune surveillance, particularly in metastatic and chemoresistant prostate cancer and breast cancer. Recently, my laboratory published our first independent research paper that identified a novel immunosuppressive mechanism by reactive nitrogen species in prostate cancer (Feng et al. PNAS. 2018). My laboratory also investigate novel genetic and molecular mechanisms and therapeutic targets in prostate cancer as well as a few rare cancers (Von Hippel-Lindau syndrome, penile squamous cell carcinoma). Our research approach integrates genetically engineered mouse models, functional genomics, preclinical and co-clinical trials, and cutting-edge methodologies (e.g. CRISPR/cas9, single cell RNA-seq, mass cytometry, high-throughput drug screening and intravital microscopy).
- e. 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, Wang YA, DePinho RA, Pettaway CA, Lu X. Effective Combinatorial Immunotherapy for Penile Squamous Cell Carcinoma. Nature Communications. In press.
- 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; 6:80-95. (*Co-first author)
- 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(7647): 728-732.
- 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.
- 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 Sep 19. pii: 201800695. doi: 10.1073/pnas.1800695115
Contribution to Science with Selected Publications
1. Prostate cancer is the most commonly diagnosed noncutaneous malignancy and the second leading cause of cancer mortality for American men. The second most common cancer in men worldwide, prostate cancer accounts for 15% of all cancers diagnosed in men globally. Using mouse models of aggressive prostate cancer, I co-discovered the massive infiltration of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. Targeting MDSCs by blocking the YAP/Cxcl5/Cxcr2 signaling axis significantly impaired tumor progression. I developed the first chimeric genetically engineered mouse (GEM) model of metastatic castration-resistant prostate cancer (CRPC). Using this model, I demonstrated that kinase inhibitors (Cabozantinib, Dactolisib, PI3K isoform-specific inhibitors) and CXCR1/2 inhibitor diminished MDSC infiltration and activities. More importantly, these drugs significantly sensitized immunotherapy-refractory metastatic CRPC to the immune checkpoint blockade therapy (anti-CTLA4 and anti-PD1 antibodies). This finding illuminates a clinical path hypothesis for using combinatorial immunotherapy to treat lethal prostate cancer. More recently, in my own laboratory, we made an independent finding that MDSCs can suppress T cells through nitrating the essential tyrosine kinase LCK. The combination of MDSC-targeted therapy and immune checkpoint blockade may prove to be an effective approach to treating a variety of cancer types, including some rare cancers. Specifically, in the first GEM model of penile squamous cell carcinoma, my preliminary results show that drugs that diminish MDSCs (cabozantinib, celecoxib) synergize significantly with immune checkpoint blockade to eradicate the tumor burden in mice.
- 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; 6:80-95. (*Co-first author) [PMID: 26701088; PMCID: PMC4707102]
- 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(7647): 728-732. [PMID: 28321130; PMCID: PMC5374023]
- 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 (#Corresponding author) [PMID: 30232256]
- 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, Wang YA, DePinho RA, Pettaway CA, Lu X#. Effective Combinatorial Immunotherapy for Penile Squamous Cell Carcinoma. Nature Communications. In press. (#Corresponding author)
2. Genetic changes and dysregulated signaling pathways play foundationally important roles in driving the oncogenesis and metastasis of prostate cancer. I have identified several important genetic and molecular mechanisms for advanced lethal prostate cancer, and the key functional players in these mechanisms are promising prognostic biomarkers and therapeutic targets for treating prostate cancer. I identified that the gene encoding the chromatin effector PYGO2 is frequently amplified in advanced prostate cancer and PYGO2 is essential for prostate cancer primary tumor growth and metastasis development in animal models.
- 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. (*Co-first author) [PMID:29352019; PMCID:PMC5795781]
- 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(7642):484-488. [PMID: 28166537; PMCID: PMC5448706]
- Lu X*, Pan X*, Wu CJ, Zhao D, Feng S, Zang Y, Lee R, Khadka S, Amin SB, Jin E, Shang X, Deng P, Luo Y, Morgenlander WR, Weinrich J, Lu X, Jiang S, Chang Q, Navone N, 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. (*Co-first author) [PMID: 29769196]
3. Breast cancer is the most common malignancy and second leading cause of cancer mortality for American women. Breast cancer mortality is caused by distant metastasis, with bone as one of the preferred organs to be colonized by breast cancer cells. Bone metastasis of breast cancer is caused by intricate tumor/osteoblast/osteoclast interactions in a “vicious signaling cycle”, understanding of which holds promise for new therapeutic opportunities. I uncovered several new mechanisms on how cancer cells hijack the normal physiology of the bone homeostatic circuits to develop osteolytic metastasis. The transition from dormant disseminated tumor cells to overt metastasis by upregulation of VCAM-1 is particularly intriguing, as it illustrates how heterotypic interactions between breast cancer cells and osteoclast progenitor cells in the bone can dictate cell fate and metastasis status.
- Lu X, Wang Q, Hu G, Van Poznak C, Fleisher M, Reiss M, Massagué J, and Kang Y. ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis. Genes & Dev. 2009; 23:1882-1894. [PMID: 19608765; PMCID: PMC2725946]
- Lu X, and Kang Y. Chemokine (C-C Motif) ligand 2 engages CCR2+ stromal cells of monocytic origin to promote breast cancer metastasis to lung and bone. J. Biol. Chem. 2009; 284: 29087-29096. [PMID: 19720836; PMCID: PMC2781454]
- Lu X, Yan C, Yuan M, Wei Y, Hu G, and Kang Y. In vivo dynamics and distinct functions of hypoxia in primary tumor growth and organotropic metastasis of breast cancer. Cancer Res. 2010; 70: 3905-3914. [PMID: 20442288; PMCID: PMC2872139]
- 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. [PMID: 22137794; PMCID: PMC3241854]
4. Cell fusion may play an active role to promote cancer progression, metastasis and immune evasion. Through a spontaneous cell fusion model, I demonstrated that metastasis tropism in a fused cell can be inherited from two parental cancer cells with distinct metastatic organo-specificity. Further study revealed a previous unknown mechanism for enhancing metastatic potential through spontaneous ploidy duplication. These studies provide new insights into the cellular mechanisms that can govern the metastatic phenotype.
- Lu X, and Kang Y. Efficient acquisition of dual metastasis organotropism to bone and lung through stable spontaneous fusion between MDA-MB-231 variants. Proc. Natl. Acad. Sci. 2009; 106:9385-9390. [PMID: 19458257; PMCID: PMC2695061]
- Lu X, Lu X, and Kang Y. Organ-specific enhancement of metastasis by spontaneous ploidy duplication and cell size enlargement. Cell Res. 2010; 20:1012–1022. [PMID: 20603645; PMCID: PMC2932852]
- Lu X, Kang Y. Cell fusion as a hidden force in tumor progression. Cancer Res. 2009; 69(22):8536-9. [PMID: 19887616; PMCID: PMC2783941]
- Lu X, and Kang Y. Cell fusion hypothesis of the cancer stem cell. In: Dittmar T and Zänker K (eds.) Cell Fusion in Health and Disease, Advances in Experimental Medicine and Biology. 2011; 714:129-40. (Book Chapter) [PMID: 21506011]
5. I led the development of the first light-inducible tamoxifen analog that can be used with CreER-LoxP system in mice to achieve single cell level genetic switch with the fine control by single or two photo light activation. This patented “Optochemogenetic” switch will find broad applications, especially in tumor and developmental biology, where localized and pattern-specific gene manipulation is of central importance to address many outstanding questions.
- 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). [PMID: 22917215; PMCID: PMC3775343]
- Lu X, Agasti S, DePinho RA, Weissleder R. Photoactivable caged tamoxifen and tamoxifen derivative molecules and methods of use thereof. US Patent # 20150093365. Issued 4/2/2015
Complete List of Published Work in MyBibliography:
I enjoy indoor and outdoor activities with my family. At my leisure time, I write Chinese poems and tune to various styles of music. Below is calligraphic rendering of a few of my poems.