Biography

Dr. Xiangdong Lyu is currently a tenure-track Assistant Professor and CPRIT Scholar in Cancer Research in the Center for Translational Cancer Research, Brown Foundation Institute of Molecular Medicine (IMM), McGovern Medical School, UTHealth-Houston.

Dr. Lyu received his B.S. from Shandong University in China, and Ph.D. from Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. During his graduate training, he elucidated the molecular mechanisms of epigenetics regulation of transcription and cell signaling transduction that are critical for Drosophila development and adult stem cell maintenance. He expanded his research to basic and translational cancer research during postdoc training at Baylor College of Medicine and MD Anderson Cancer Center, where he used extensive preclinical patient-derived xenograft (PDX) and genetically engineered mouse (GEM) models to study proteotoxic stress responses in cancer therapy resistance.

At UTHealth, the Lyu lab focuses on understanding how cancer cells sense and respond to stresses from the tumor microenvironment and therapeutic interventions. By investigating the molecular mechanisms of key stress responses and signaling pathways that drive tumorigenesis and resistance to targeted therapy and chemotherapy, the Lyu lab aims to develop innovative, mechanism-based strategies to overcome these resistances.

Professional Highlights

  • CPRIT Scholar in Cancer Research, Cancer Prevention & Research Institute of Texas, 2025
  • ExCEL Scholar Award, Montefiore Einstein Comprehensive Cancer Center, 2024
  • DOD Breakthrough Fellowship Award, 2019-2023
  • Dean’s Award of Excellence, Baylor College of Medicine, 2019
  • Excellent Graduates, Chinese Academy of Sciences, 2016
  • Selected poster presentation at Annual Drosophila Research Conference, Chicago, IL, 2015
  • National Scholarship for graduate students, 2015
  • Excellent Poster Award, Asia-Pacific Developmental Biology Conference, 2015
  • Di’Ao Scholarship, Chinese Academy of Sciences, 2014
  • Merit student, Chinese Academy of Sciences, 2014
  • Excellent Poster Award, Annual Conference of State Key Laboratory of Cell Biology, 2013
  • Excellent Poster Award, Annual Conference of Institute of Biochemistry and Cell Biology, 2012
  • First Class Excellent Undergraduate Scholarship, Shandong University, 2008-2009
  • National Encouragement Scholarship, 2008-2009
  • Merit Student, Shandong University, 2008-2009

Grant & Contract Support

Date: 2025-2029

Title: Recruitment of First-Time, Tenure-Track Faculty Members

Funding Source: Cancer Prevention Research Institute of Texas

Role: PI

ID: RR250052

 

Date: 2019-2023

Title: Breast Cancer Breakthrough Fellowship Award

Funding Source: Department of Defense/Congressionally Directed Medical Research Programs

Role: PI

ID: W81XWH-19-1-0035

Education

B.S. in Biotechnology
School of Life Science, Shandong University, China, 2006-2010
Ph.D. in Developmental Biology
Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China, 2010-2016
DOD Breakthrough Postdoctoral Fellow
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA, 2017-2024
Research Scientist
Department of Experimental Therapeutics, James. P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 2024-2025

Areas of Interest

Research Interests

Despite the increasing numbers of effective agents for treating cancers, drug resistance remains the major barrier to cure and long-term disease control. Our research focuses on understanding the fundamental mechanisms driving cancer therapy resistance. Specifically, we aim to uncover how cancer cells sense stress from therapeutic interventions, respond, adapt, and communicate with the tumor microenvironment to ultimately survive drug treatment. Our long-term goal is to identify conceptual and effective targets to prevent and overcome these resistances.

We employ a unique collection of preclinical PDX and GEM models that mimic human cancers in combination with cutting-edge, unbiased multi-omic approaches, including quantitative proteomics, chemical proteomics, ribosome profiling, RNA-seq, CRISPR-Cas9 screening, and biochemical assays. These unbiased multi-omic approaches and preclinical models ensure our studies are effective and conclusions are insightful.

 

Targeted therapy resistance:

KRAS is the most frequently mutated oncogene in human cancers. While inhibitors targeting oncogenic KRASG12C have received accelerated FDA approval, resistance to these KRAS inhibitors (KRASi) is common and understanding the mechanisms that mediate this resistance is critical to the development of more effective therapies and the prevention of recurrence. Dr. Lyu discovered that proteostasis reprogramming – a cellular process that maintains protein homoestasis – is a key mechanism driving resistance to KRASi. He further identified the ancient endoplasmic reticulum stress sensor IRE1α as a key convergent point for multiple KRASi resistance mechanisms, critical to re-establish proteostasis. Targeting IRE1α with ORIN1001, a selective IRE1α RNase inhibitor that demonstrated safety and tolerability in a phase I clinical trial (NCT03950570), collapses the reprogrammed proteostasis and overcomes resistance (Science, 2023).

Given that proteostasis is orchestrated by a complex network of nearly 3,000 genes involved in protein synthesis, folding, remodeling, and degradation, and targeting IRE1α achieves complete and durable response in only ~60% of the preclinical models when combined with a KRAS inhibitor, this highlights the need to further dissect the heterogenous mechanisms that drive resistance to KRAS inhibitors. Ongoing efforts in our lab aim to:

1) Elucidate the crosstalk between compartment-specific subcellular proteostasis networks;

2) Systemically dissect tumor-intrinsic drivers of proteostasis network reprogramming;

3) Explore interactions between cancer cells and the tumor microenvironment.

In addition to our studies in oncogenic KRAS-driven pancreatic and lung cancer models, our research program can be extended to various physiological or pathological contexts, including resistance to EGFR-KRAS targeted therapies in colorectal cancer, EGFR targeted therapy in lung cancer, HER2 targeted therapy in breast cancer.

 

Chemotherapy resistance:

Conventional chemotherapy remains the main systemic treatment option for triple-negative breast cancer (TNBC), which is characterized by lack of estrogen receptor (ER) and progesterone receptor (PR) expression and human epidermal growth factor receptor 2 (HER2) amplification. However, about half of TNBC patients with localized disease treated with neoajuvant chemotherapy fail to achieve a pathologic complete response, and the residual cancer burden leads to a high risk of metastasis and mortality. The FDA approved combined use of the anti-PD-1 inhibitor pembrolizumab with chemotherapy to treat high-risk TNBC. However, many patients with immunologically cold TNBC still have limited or no response to immune checkpoint inhibitors. Therefore, there is an unmet need to understand mechanisms of how residual TNBC cells survive chemotherapy to achieve better therapeutic efficacy with rationalized combination therapy.

Our unpublished data has shown a cancer cell metabolism reprogramming in response to conventional chemotherapy, critical for residual TNBC cells survival. Ongoing efforts will elucidate mechanisms driving the metabolism reprograming and develop mechanism-based strategies to prevent recurrence.

Publications

Visit the PubMed profile page

First and co-first author papers (*: co-first author.)

  1. Lv X*, Lu X*, Cao J*, Luo Q, Ding Y, Peng F, Pataer A, Lu D, Han D, Malmberg E, Chan DW, Wang X, Savage SR, Mao S, Yu J, Peng F, Yan L, Meng H, Maneix L, Han Y, Chen Y, Yao W, Chang EC, Catic A, Lin X, Miles G, Huang P, Sun Z, Burt B, Wang H, Wang J, Yao QC, Zhang B, Roth JA, O’Malley B, Ellis MJ, Rimawi MF, Ying H, and Chen X, “Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors”. Science, 2023; 381, eabn4180, [PMID: 37676964] [PMC10720158]
    • Research Watch: Proteostasis Network Modulation Promotes Resistance to KRAS Inhibitors. Cancer Discovery, 2023 Sep 15.
    • Research Highlight: Eccleston A, Rewired proteostasis in KRAS inhibitor resistance, Nature Reviews Drug Discovery, 2023 Sep 27.
    • News & Buzz: Decoding the proteostasis network in resistance to KRAS inhibitors, The Innovation, 2023 Oct 18.
    • Spotlight: Addicted to proteostasis: How KRAS-driven cancers acquire resistance to clinical KRAS inhibitors, Cell Chemical Biology, 2023 Nov 16.
  2. Lv X, Han Z, Chen H, Yang B, Yang X, Xia Y, Pan C, Fu L, Zhang S, Han H, Wu M, Zhou Z, Zhang L, Li L, Wei G, and Zhao Y, “A positive role for polycomb in transcriptional regulation via H4K20me1”. Cell Research, 2016; 26, 529-542, [PMID: 27002220]
  3. Lv X*, Pan C*, Zhang Z, Xia Y, Chen H, Zhang S, Guo T, Han H, Song H, Zhang L, and Zhao Y, “SUMO regulates somatic cyst stem cell maintenance and directly targets the Hedgehog pathway in adult Drosophila testis”. Development, 2016; 143, 1655-1662, [PMID: 37013244]
  4. Lv X*, Chen H*, Zhang S, Zhang Z, Pan C, Xia Y, Fan J, Wu W, Lu Y, Zhang L, Wu H, and Zhao Y, “Fsh-Pc-Sce complex mediates active transcription of Cubitus interruptus (Ci)”. Journal of Molecular Cell Biology, 2018; 10, 437-447, [PMID: 29432547]
  5. Lv X*, Chen H*, Zhang S, Zhang Z, Pan C, Xia Y, Fan J, Wu W, Lu Y, Zhang L, Wu H, and Zhao Y, “Distinct functions of polycomb group proteins in regulating Ci transcription in developing Drosophila”. Journal of Molecular Cell Biology, 2018; 10, 475-478, [PMID: 29924323]
  6. Lv X*, Dobrolecki LE*, Ding Y, Rosen JM, Lewis MT, and Chen X, “Orthotopic Transplantation of Breast Tumors as Preclinical Models for Breast Cancer”. Journal of Visualized Experiments, 2020; e61173, [PMID: 32478757] [PMC7927877]
  7. Lv X, Fu L, and Zhao Y, “aPKC iota/lambda: a potential target for the therapy of Hh-dependent and Smo-inhibitor-resistant advanced BCC”. Acta Biochim Biophys Sin, 2013; 45, 610-611, [PMID: 23685738]
  8. Shi D*, Lv X*, Zhang Z, Yang X, Zhou Z, Zhang L, and Zhao Y, “Smoothened oligomerization/higher order clustering in lipid rafts is essential for high Hedgehog activity transduction”. Journal of Biological Chemistry, 2013; 288, 12605-12614, [PMID: 23532857]
  9. Huang S*, Zhang Z*, Zhang C*, Lv X*, Zheng X, Chen Z, Sun L, Wang H, Zhu Y, Zhang J, Yang S, Lu Y, Sun Q, Tao Y, Liu F, Zhao Y, and Chen D, “Activation of Smurf E3 ligase promoted by smoothened regulates hedgehog signaling through targeting patched turnover”. PLoS Biology, 2013; 11, e1001721, [PMID: 24302888]

Co-author papers

  1. Zhang Z, Lv X, Yin WC, Zhang X, Feng J, Wu W, Hui CC, Zhang L, and Zhao Y, “Ter94 ATPase complex targets k11-linked ubiquitinated ci to proteasomes for partial degradation”. Developmental Cell, 2013; 25, 636-644, [PMID: 23747190]
  2. Zhang Z, Lv X, Jiang J, Zhang L, and Zhao Y, “Dual roles of Hh signaling in the regulation of somatic stem cell self-renewal and germline stem cell maintenance in Drosophila testis”. Cell Research, 2013; 23, 573-576, [PMID: 23419515] [PMC3616438]
  3. Zheng C, Wei Y, Zhang P, Xu L, Zhang Z, Lin K, Hou J, Lv X, Ding Y, Chiu Y, Jain A, Islam N, Malovannaya A, Wu Y, Ding F, Xu H, Sun M, Chen X, and Chen Y, “CRISPR/Cas9 screen uncovers functional translation of cryptic lncRNA-encoded open reading frames in human cancer”. Journal of Clinical Investigation, 2023; 133, [PMID: 36856111] [PMC9974104]
  4. Zheng C, Wei Y, Zhang Q, Sun M, Wang Y, Hou J, Zhang P, Lv X, Su D, Jiang Y, Gumin J, Sahni N, Hu B, Wang W, Chen X, McGrail DJ, Zhang C, Huang S, Xu H, Chen J, Lang FF, Hu J, and Chen Y, “Multiomics analyses reveal DARS1-AS1/YBX1-controlled posttranscriptional circuits promoting glioblastoma tumorigenesis/radioresistance”. Science Advances, 2023; 9, eadf3984, [PMID: 37540752] [PMC10403220]
  5. Zhao N, Cao J, Xu L, Tang Q, Dobrolecki LE, Lv X, Talukdar M, Lu Y, Wang X, Hu DZ, Shi Q, Xiang Y, Wang Y, Liu X, Bu W, Jiang Y, Li M, Gong Y, Sun Z, Ying H, Yuan B, Lin X, Feng XH, Hartig SM, Li F, Shen H, Chen Y, Han L, Zeng Q, Patterson JB, Kaipparettu BA, Putluri N, Sicheri F, Rosen JM, Lewis MT, and Chen X, “Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer”. Journal of Clinical Investigation, 2018; 128, 1283-1299, [PMID: 29480818] [PMC5873887]
  6. Xu L, Peng F, Luo Q, Ding Y, Yuan F, Zheng L, He W, Zhang S S, Fu X, Liu J, Mutlu A S, Wang S, Nehring R B, Li X, Tang Q, Li C, Lv X, Dobrolecki L E, Zhang W, Han D, Zhao N, Jaehnig E, Wang J, Wu W, Graham D A, Li Y, Chen R, Peng W, Chen Y, Catic A, Zhang Z, Zhang B, Mustoe A M, Koong A C, Miles G, Lewis M T, Wang M C, Rosenberg S M, O’Malley B W, Westbrook T F, Xu H, Zhang X H, Osborne C K, Li J B, Ellis M J, Rimawi M F, Rosen J M, and Chen X, “IRE1alpha silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer”. Cell, 2024; [PMID: 39419025]
  7. Sun M, Wang Y, Zheng C, Wei Y, Hou J, Zhang P, He W, Lv X, Ding Y, Liang H, Hon CC, Chen X, Xu H, and Chen Y, “Systematic functional interrogation of human pseudogenes using CRISPRi”. Genome Biology, 2021; 22, 240, [PMID: 34425866] [PMC8381491]
  8. Liu X, Yu J, Xu L, Umphred-Wilson K, Peng F, Ding Y, Barton BM, Lv X, Zhao MY, Sun S, Hong Y, Qi L, Adoro S, and Chen X, “Notch-induced endoplasmic reticulum-associated degradation governs mouse thymocyte beta-selection”. eLife, 2021; 10, [PMID: 34240701] [PMC8315795]
  9. Mao F, Yang X, Fu L, Lv X, Zhang Z, Wu W, Yang S, Zhou Z, Zhang L, and Zhao Y, “The Kto-Skd complex can regulate ptc expression by interacting with Cubitus interruptus (Ci) in the Hedgehog signaling pathway”. Journal of Biological Chemistry, 2014; 289, 22333-22341, [PMID: 24962581] [PMC4139242]
  10. Zhang S, Zhao J, Lv X, Fan J, Lu Y, Zeng T, Wu H, Chen L, and Zhao Y, “Analysis on gene modular network reveals morphogen-directed development robustness in Drosophila”. Cell Discovery, 2020; 6, 43, [PMID: 32637151] [PMC7324402]
  11. Cheng L, Zhang X, Wang Y, Gan H, Xu X, Lv X, Hua X, Que J, Ordog T, and Zhang Z, “Chromatin Assembly Factor 1 (CAF-1) facilitates the establishment of facultative heterochromatin during pluripotency exit”. Nucleic Acids Research, 2019; 47, 11114-11131, [PMID: 31586391] [PMC6868363]
  12. Pan C, Xiong Y, Lv X, Xia Y, Zhang S, Chen H, Fan J, Wu W, Liu F, Wu H, Zhou Z, Zhang L, and Zhao Y, “UbcD1 regulates Hedgehog signaling by directly modulating Ci ubiquitination and processing”. EMBO Reports, 2017; 18, 1922-1934, [PMID: 28887318] [PMC5666607]
  13. Zhang S, Pan C, Lv X, Wu W, Chen H, Wu W, Wu H, Zhang L, and Zhao Y, “Repression of Abd-B by Polycomb is critical for cell identity maintenance in adult Drosophila testis”. Scientific Reports, 2017; 7, 5101, [PMID: 28698559] [PMC5506049]
  14. Fu L, Lv X, Xiong Y, and Zhao Y, “Investigation of Protein-Protein Interactions and Conformational Changes in Hedgehog Signaling Pathway by FRET”. Methods in Molecular Biology, 2015; 1322, 61-70, [PMID: 26179039]
  15. Han H, Pan C, Liu C, Lv X, Yang X, Xiong Y, Lu Y, Wu W, Han J, Zhou Z, Jiang H, Zhang L, and Zhao Y, “Gut-neuron interaction via Hh signaling regulates intestinal progenitor cell differentiation in Drosophila”. Cell Discovery, 2015; 1, 15006, [PMID: 27462407] [PMC4860846]
  16. Yang X, Mao F, Lv X, Zhang Z, Fu L, Lu Y, Wu W, Zhou Z, Zhang L, and Zhao Y, “Drosophila Vps36 regulates Smo trafficking in Hedgehog signaling”. Journal of Cell Science, 2013; 126, 4230-4238, [PMID: 23843610]
  17. Zhang Z, Feng J, Pan C, Lv X, Wu W, Zhou Z, Liu F, Zhang L, and Zhao Y, “Atrophin-Rpd3 complex represses Hedgehog signaling by acting as a corepressor of CiR”. Journal of Cell Biology, 2013; 203, 575-583, [PMID: 24385484] [PMC3840934]