Principal Investigator

Xin Lu

Xin Lu, Ph.D.

Trained as a molecular biologist with Dr. Yibin Kang at Princeton University and subsequently as postdoc fellow with Dr. Ronald DePinho at Dana-Farber Cancer Institute and MD Anderson Cancer Center, my main research goal is to develop novel insights into the genomic, genetic and molecular mechanisms of tumor progression, tumor immunology and treatment resistance, and apply such knowledge to enhance efficacy of therapeutic intervention to benefit patients. My recent research is centered on mechanistic understanding of myeloid-derived suppressor cells (MDSCs) and developing strategies on targeting MDSCs to enhance immune checkpoint blockade. Most recently, I developed an efficient preclinical platform to test combinatorial immunotherapy for metastatic castration-resistant prostate cancer (mCRPC) and discovered that inactivating MDSCs can exert dramatic synergistic efficacy in treating mCPRC when combined with immune checkpoint blockade. In addition, my research program on prostate cancer functional genomics through in vivo ORF screen has identified new epigenetic regulatory mechanisms of prostate cancer bone metastasis and established a goldmine of new prostate cancer genes for deep mechanistic investigation and clinical translation. I am also interested in rare cancers and have developed the first transgenic mouse models of penile cancer. Continuation with deeper mechanistic understanding and translational application on the aforementioned lines of research represents the current and near future research interests of my laboratory at University of Notre Dame.

Contribution to Science with Selected Publications

1. My studies and publications in PhD addressed important questions on molecular understanding of tumor/osteoblast/osteoclast interactions in the “vicious cycle” of breast cancer bone metastasis. Through building in vitro and in vivo cell-cell interaction models in the context of skeletal metastasis, I uncovered several new mechanisms on how cancer cells hijack the normal physiology of bone homeostatic circuits to develop osteolytic and lethal metastasis with translational potential for biomarkers and therapeutic targets.

  • 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. (Cover highlight) Editorial by: Guise TA. (2009) Gens & Dev., 23:2117-23.
  • 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.
  • 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.
  • 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) Most downloaded paper in Dec, 2011. Editorial by: Hynes RO. (2011) Cancer Cell, 20:689-690. Seton-Rogers S. (2011) Nature Reviews Cancer, 12: 920. Haas MJ. (2012) SciBX, 5(2):1-2.

2. In my PhD, I also investigated a less studied area yet one with paradigm-shifting implication on how we view cancer – the function of cell fusion in cancer progression and metastasis. Through a spontaneous cell fusion model, I demonstrated that metastasis tropism as a core feature of distant metastasis 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 provided new angles on metastasis theory and the positive feedback on them was reflected by me being the only invited speaker with non-faculty title in the first NCI’s workshop on Exosomes and Cell Fusion, Rockville, MD, 2010.

  • 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.
  • 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.
  • 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)

3. My research in Postdoc and Instructor periods centers on the molecular and genetic understanding of prostate cancer with genetically engineered mouse model (GEMM) as the core toolset for investigation. I focused on two areas. In one area, I initiated the tumor microenvironment (TME) program of prostate cancer research in Dr. DePinho’s lab and co-discovered the massive infiltration of MDSCs into the TME in aggressive prostate cancer and targeting MDSCs led to significant tumor regression. I also led the development of the first chimeric GEMM of metastatic CRPC and identified that combination of MDSC-targeted agents and immunotherapy provided drastic synergistic efficacy against mCRPC. In another area, I led a group effort in identification of new prostate cancer genes through in vivo functional screen of frequently amplified genes and found one gene amplified in 1q21 can significantly contribute to the pathogenesis of metastasis prostate cancer. I also developed the first GEMMs of penile cancer, a rare but fatal cancer, and identified potential combination therapy approaches to treating penile cancer.

  • 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. Editorial by: Nat Rev Urol. 2017 Mar 21. doi: 10.1038/nrurol.2017.44. Cancer Discov. 2017 Mar 31. doi: 10.1158/2159-8290.CD-RW2017-064.

4. As an aficionado of new technology, 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.

  • a. 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).
  • 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

Extra-professional life

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.

Chinese Poems