Assistant Professor in Pathology
Member of the Duke Cancer Institute
Lee Lab Overview
Radiation Injury, Regeneration and Carcinogenesis
The overall goal of the Lee lab’s research program is to improve the survivorship of cancer patients by minimizing acute and long-term side effects of radiation therapy. We are also investigating novel medical countermeasures against acute radiation syndrome in the scenarios of nuclear terrorism.
Current Research Interests
Utilizing sophisticated mouse models, we aim to study 1) critical signaling pathways that regulate the regeneration of normal tissues following radiation injury; 2) cell-autonomous and non-cell-autonomous mechanisms underlying the development of radiation-induced cancer.
- Radiation-induced hematologic malignancies and clonal hematopoiesis
- Radiation-induced acute and chronic intestinal injury
- Radiation response of rectal cancer (collaboration with Jatin Roper, MD)
Toward Understanding Mechanisms for the Development of Radiation-Induced Hematologic Malignancies
Exposure of the bone marrow (BM) to ionizing radiation from cancer therapy or a nuclear disaster is associated with a significant increase in the risk of developing secondary hematologic malignancies. Due to an ever-increasing number of cancer survivors and the threat of nuclear terrorism, there is an unmet need to develop effective strategies for risk assessment, prevention and mitigation of radiation-induced hematologic malignancies. The long-term goal of the Lee Lab's research program is to study how ionizing radiation alters the microenvironment and cell competition within the stem/progenitor pool to promote the development of secondary hematologic cancers.
Project 1: Ionizing radiation promotes the expansion of premalignant cells in the thymus
Experimentally, ionizing radiation effectively induces thymic (T-cell) lymphomas in wild-type mice. Although mouse models of radiation-induced thymic lymphomas have been used to study various aspects of radiation and cancer biology, the fundamental mechanisms for the development of radiation-induced T-lymphoma remain incompletely understood. The goal of this project is to use novel genetically engineered mice and next-generation genetic tools to investigate how radiation impacts initiation, expansion and malignant transformation of thymic progenitor into thymic lymphomas.
Proposed models of radiation-induced thymic lymphoma. We hypothesize that radiation promotes lymphoma formation by decreasing cell competition from BM-derived hematopoietic stem/progenitor cells (HSPCs) (Aim 1), which promotes clonal expansion of thymic-intrinsic progenitors with oncogenic potential (Aim 2) that undergoes genetic and epigenetic evolution for malignant transformation (Aim 3).
Project 2: Minimizing the risk of therapy-related myeloid neoplasms: targeting p53 mutant cells
The goal of this project is to reduce the risk of developing therapy-related myeloid neoplasms (t-MNs) in patients who receive chemotherapy and/or radiotherapy. About 30% of t-MNs evolve from rare founding clones that harbor mutations in the tumor suppressor p53. We are using mouse models to investigate novel strategies that can either prevent the expansion of p53 mutant cells or selectively deplete these cells before they undergo malignant transformation.
Developing novel strategies to ameliorate radiation-induced gastrointestinal toxicity
Delivery of adequate doses of radiation therapy to treat tumors in the abdomen is often limited by normal tissue toxicity of the gastrointestinal (GI) tract. The GI acute radiation syndrome (GI-ARS) occurs after high dose abdominal radiation exposure, which induces extensive damage to crypt stem cells of the small intestines. Severe damage to intestinal stem cells impairs regeneration of the intestinal epithelium, which can result in atrophy of the villi, loss of mucosal barrier, and sepsis. Currently, there are no drugs approved by the US FDA to specifically treat the GI-ARS beyond standard supportive care. Therefore, we are interested in developing novel therapeutic strategies that preserve the crypt cells and promote regeneration of the GI epithelium after radiation.
- Lee CL, Castle KD, Moding EJ, Blum JM, Williams N, Luo L, Ma Y, Borst L, Kim Y, Kirsch DG. Acute DNA Damage Activates the Tumor Suppressor p53 to Promote Radiation-induced Lymphoma. Nature Communications. 2015 Sep 24;6:8477. PMCID: PMC4586051
- Moding EJ, Min HD, Castle KD, Ali M, Woodlief L, Williams N, Ma Y, Kim Y, Lee CL, Kirsch DG. An Extra Copy of p53 Suppresses Development of Spontaneous Kras-driven but not Radiation-Induced Cancer. JCI Insight. 2016 Jul 7;1(10). pii:e86698. PMCID:PMC4955525
- Lee CL*, Mowery YM*, Daniel AR*, Zhang D, Sibley AB, Delaney JR, Wisdom AJ, Qin X, Wang X, Caraballo I, Gresham J, Luo L, Van Mater D, Owzar K, Kirsch DG. Mutational landscape in genetically engineered, carcinogen-induced, and radiation-induced mouse sarcoma. JCI Insight. 2019 May 21;5. pii: 128698. doi: 10.1172/jci.insight.128698. PubMed PMID: 31112524. (*Equal contribution)
- Hasapis S, Caraballo I, Lee CL. Transplantation of unirradiated bone marrow cells following total-body irradiation prevents the development of thymic lymphoma in mice through niche competition. Radiation Research. 2021 Mar 1;195(3):301-306. doi:10.1667/RADE-20-00221.1. PMID: 33347573; PMCID: PMC8240018.
- Lee CL*, Brock KD, Hasapis S, Zhang D, Sibley AB, Qin X, Gresham JS, Caraballo I, Luo L, Daniel AR, Hilton MJ, Owzar K, and Kirsch DG*. Whole-exome sequencing of radiation-induced thymic lymphoma in mouse models identifies Notch1 activation as a driver of p53 wild-type lymphoma. Cancer Research. 2021 May 25:canres.2823.2020.doi: 10.1158/0008-5472.CAN-20-2823. Epub ahead of print. PMID: 34035082. (*Co-senior authors)
Normal tissue radiation injury
- Lee CL, Moding EJ, Cuneo KC, Li Y, Sullivan JM, Mao L, Washington I, Jeffords LB, Rodrigues RC, Ma Y, Das S, Kontos CD, Kim Y, Rockman HA, Kirsch DG. p53 Functions in Endothelial Cells to Prevent Radiation-Induced Myocardial Injury in Mice. Science Signaling. 2012 Jul 24; 5(234). PMCID: PMC3533440
- Lee CL, Min H, Befera N, Clark D, Qi Y, Das S, Johnson GA, Badea CT, Kirsch DG. Assessing Cardiac Injury in Mice with Dual Energy-microCT, 4D-microCT, and microSPECT Imaging After Partial Heart Irradiation. International Journal of Radiation Oncology, Biology, Physics. 2014 Mar 1;88(3):686-693. PMCID: PMC3985387
- Lee CL*, Lento WE*, Castle KD, Chao NJ, Kirsch DG. Inhibiting Glycogen Synthase Kinase-3 Mitigates the Hematopoietic Acute Radiation Syndrome in Mice. Radiation Research. 2014 May; 181(5):445-451. PMCID: PMC4080719 (*Equal contribution)
- Lee CL, Oh P, Xu E, Ma Y, Kim Y, Daniel AR, Kirsch DG. Blocking cyclin-dependent kinase 4/6 during single dose vs. fractionated radiation therapy leads to opposite effects on acute gastrointestinal toxicity in mice. International Journal of Radiation Oncology, Biology, Physics. 2018 Jul 26. pii: S0360-3016(18)31645-6. doi: 10.1016/j.ijrobp.2018.07.192. [Epub ahead of print] PubMed PMID: 30056081
- Lee CL, Daniel AR, Holbrook M, Brownstein J, Silva Campos LD, Hasapis S, Ma Y, Borst LB, Badea CT, Kirsch DG. Sensitization of Vascular Endothelial Cells to Ionizing Radiation Promotes the Development of Delayed Intestinal Injury in Mice. Radiation Research. 2019 Sep;192(3):258-266. doi: 10.1667/RR15371.1. Epub 2019 Jul 2. PubMed PMID: 31265788.
- Lee CL*, Lee JW*, Daniel AR, Holbrook M, Hasapis S, Wright AO, Brownstein J, Da Silva Campos L, Ma Y, Mao L, Abraham D, Badea CT, Kirsch DG. Characterization of cardiovascular injury in mice following partial-heart irradiation with clinically relevant dose and fractionation. Radiotherapy and Oncology. 2021 Feb 2:S0167-8140(21)00025-6. doi: 10.1016/j.radonc.2021.01.023. Epub ahead of print. PMID: 33545252. (*Equal contribution)
- Sheahan BJ, Freeman AN, Keeley TM, Samuelson LC, Roper J, Hasapis S, Lee CL, Dekaney CM. Epithelial regeneration after doxorubicin arises primarily from early progeny of active intestinal stem cells. Cellular Molecular Gastroenterology Hepatology. 2021 Feb 8:S2352-345X(21)00021-7. doi: 10.1016/j.jcmgh.2021.01.015. Epub ahead of print. PMID: 33571711.
- Lee CL, Wright AO, Lee JW, Brownstein J, Hasapis S, Satow S, Da Silva Campos L, Williams N, Ma Y, Luo L, Johnson T, Daniel AR, Harrison WT, Oldham M and Kirsch DG. Sensitization of endothelial cells to ionizing radiation exacerbates delayed radiation myelopathy in mice. Radiation Research. 2021 Nov 1;197(3):0. doi:10.1667/RADE-21-00166.1. PMID: 34724704; PMCID: PMC8567311.
Tumor responses to radiation therapy
- Lee CL*, Moding EJ*, Huang X, Li Y, Woodlief LZ, Rodrigues RC, Ma Y, Kirsch DG. Generation of Primary Tumors with Flp Recombinase in FRT-flanked p53 Mice. Disease, Models, and Mechanisms. 2012 May; 5(3):397-402. PMCID: PMC3339833 (*Equal contribution)
- Moding EJ, Lee CL, Castle KD, Oh P, Mao L, Zha S, Min HD, Ma Y, Das S, Kirsch DG. ATM Deletion with Dual Recombinase Technology Preferentially Radiosensitizes Tumor Endothelium. Journal of Clinical Investigation. 2014 Aug 1; 124(8):3325-38. PMCID: PMC4109553
- Moding EJ, Castle KD, Perez BA, Oh P, Min HD, Norris H, Ma Y, Cardona DM, Lee CL, Kirsch DG. Tumor Cells, but not Endothelial Cells, Mediate Eradication of Primary Sarcomas by Stereotactic Body Radiation Therapy. Science Translational Medicine. 2015 Mar 11;7(278): 278ra34. PMCID: PMC4360135
- Torok JA, Oh P, Castle KD, Reinsvold M, Ma Y, Luo L, Kuo HC, Lee CL, Kirsch DG. Atm deletion in tumor but not endothelial cells improves radiation response in a primary mouse model of lung adenocarcinoma. Cancer Research. 2018 Oct 12. pii: canres.3103.2017. doi: 10.1158/0008-5472.CAN-17-3103. [Epub ahead of print] PubMed PMID: 30315114.
For a complete list of published work, click here.
Lee Lab – Alumni
- Davis Brock, BS
Research Technician II
- Isibel Caraballo, BS
Research Technician II
- Stephanie Hasapis, BS, LAT
Lab Research Analyst I; Mouse Colony Manager
- Jessica Lee, MD
- Reynier David Rodriguez Rosales
OPSD PRIME Academy 2022
- Abdul-Rahman Saleh
OPSD PRIME Academy 2021
- Sloane Satow