Principal Investigator

Xin Lu

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 12 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. My laboratory is also identifying 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 in animal models, and cutting-edge methodologies (e.g. CRISPR/cas9, single cell RNA-seq, mass cytometry, high-throughput and intravital microscopy).

  • 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.
  • 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, 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.

Contribution to Science with Selected Publications

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 the 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.
  • 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. 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.

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. 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)

My researches as a postdoctoral fellow and an Instructor focused on the understanding of prostate cancer genetics and tumor microenvironment using genetically engineered mouse models (GEMMs) of metastatic prostate adenocarcinoma. I launched the tumor microenvironment (TME) program of prostate cancer research in Dr. DePinho’s lab and co-discovered the massive infiltration of myeloid-derived suppressor cells (MDSCs) into the TME in aggressive prostate cancer. Targeting MDSCs by blocking the YAP/Cxcl5/Cxcr2 signaling axis significantly impaired tumor progression. My follow-up study on MDSCs in prostate cancer led to my most exciting publication as an Instructor: I developed the first chimeric GEMM of metastatic castration-resistant prostate cancer (CRPC), using which I demonstrated that multikinase inhibitors (Cabozantinib, Dactolisib, and PI3K isoform-specific inhibitors) that diminish MDSC infiltration and activities significantly sensitize 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. In my studies of prostate cancer genetics, using GEMMs I discovered the surprising opposing functions of TGFβ and BMP signaling pathways during prostate tumor progression. I also identified a number of novel prostate cancer genes through in vivo functional screen of recurrent amplicons. Last but not least, my avid and continued interests in rare cancers led to the development of the first GEMM of penile squamous cell carcinoma, a rare but fatal disease, and identification of potential combination therapy approach 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.
  • 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.  

During my Postdoctoral fellowship, 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).
  • 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 (24 publications)


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