Chuan-Yuan Li

Overview:

Dr. Li is the Vice Chair for Research in the Dept. of Dermatology. Some of the areas that his laboratory conducts research on include:
•Tumor response to therapy, with special emphasis on skin cancer such as melanoma and squamous cell carcinoma where current treatment outcomes are dismal;
•Stem cell and regenerative medicine, we will conduct research to investigate novel mechanisms of stem cell biology so that knowledge gained can be translated into regenerative medicine;
•Mechanisms of carcinogenesis, with emphasis on skin cancers, so that better strategies could be devised to prevent and treat these cancers.

Within these broad areas we have different ongoing research projects. Examples of some of the research projects include:

Unconventional roles of caspases in tumor response to chemotherapy or radiotherapy. A recent area of our laboratory has been the relationship of cell death and repopulation in tumors undergoing radiation and chemotherapy. In our studies, we discovered that cell death is a key trigger for tumor cell repopulation in radiation and chemotherapy. Unexpectedly, caspase 3, which is an executioner in cell death, positively regulate paracrine signaling from dying cells to stimulate proliferation of surviving tumor cells. Furthermore, we found that higher levels of pretreat caspase 3 activation is correlated with worse outcome in head and neck and breast cancers. This is again quite unexpected and contrary to established paradigm. We are currently actively studying the relevance of this mechanism in other malignancies including melanoma. We believe such studies will not only yield promising novel treatments for cancer but also new biomarkers of diagnostic or prognostic values.

Positive roles of apoptosis in wound healing and tissue regeneration. Another area of our research is the relationship between apoptosis and wound healing/tissue regeneration. In our recent research we discovered that cellular apoptosis, in particular, apoptotic caspases 3&7, play key roles in promoting skin wound healing and tissue regeneration. We named this pathway the “Phoenix Rising” pathway for wound healing and tissue regeneration. We are actively studying this mechanism with the hope that knowledge gained could be used for regenerative medicine.

Molecular factors involved in stem cell biology regulation and trans-differentiation. Recently our lab started to investigate molecular mechanisms involved in the maintenance and self-renewal of stem cells. Our efforts led to the discovery that caspases 8&3 play critical roles in the induction of pluripotent stem cells from human fibroblasts. We are in the process of dissecting additional roles of caspases in embryonic stem cells.

Direct reprogramming of one differentiated cell type into another differentiated cell type. Recently, we have been able to directly reprogram human fibroblast cells into dopaminergic neurons, which have great potential in Parksinson’s Disease. We are actively pursuing similar studies to reprogram skin fibroblasts into various cells of interest, including other skin cells, through direct reprogramming.

Positions:

Professor of Dermatology

Dermatology
School of Medicine

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Regeneration Next Initiative

Regeneration Next Initiative
School of Medicine

Education:

B.S. 1987

Chinese Academy of Sciences (China)

D.Sc. 1992

Harvard University

Grants:

Dissecting mechanism(s) by which ionizing radiation promotes clonal expansion of premalignant cells in the thymus

Administered By
Radiation Oncology
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

K63-Ubiquitin-mediated cell signal regulation in epidermis

Administered By
Dermatology
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Necroptotic genes in cancer cellular response to radiation

Administered By
Dermatology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Pro-oncogenic roles of apoptotic caspases

Administered By
Dermatology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

The "Phoenix Rising" pathway of tumor repopulation during radiotherapy

Administered By
Dermatology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Limited MOMP, ATM, and their roles in carcinogenesis and cancer treatment.

Limited mitochondria outer membrane permeability (MOMP) is a novel biological process where mammalian cells initiate the intrinsic apoptosis pathway with increased mitochondrial permeability but survive. One of the major consequences of limited MOMP is apoptotic endonuclease-induced DNA double strand breaks. Recent studies indicate that these DNA double stand breaks and ensuing activation of DNA damage response factors such as ATM play important but previously underappreciated roles in carcinogenesis and tumor growth. Furthermore, novel non-canonical roles of DNA repair factors such as ATM in tumor growth and treatment are also emerging. In this review, we try to summarize recent findings on this newly revealed link between DNA double strand break repair and cell death pathways.
Authors
Bao, X; Liu, X; Li, F; Li, C-Y
MLA Citation
Bao, Xuhui, et al. “Limited MOMP, ATM, and their roles in carcinogenesis and cancer treatment.Cell Biosci, vol. 10, 2020, p. 81. Pubmed, doi:10.1186/s13578-020-00442-y.
URI
https://scholars.duke.edu/individual/pub1448433
PMID
32566127
Source
pubmed
Published In
Cell & Bioscience
Volume
10
Published Date
Start Page
81
DOI
10.1186/s13578-020-00442-y

JMJD6 cleaves MePCE to release positive transcription elongation factor b (P-TEFb) in higher eukaryotes.

More than 30% of genes in higher eukaryotes are regulated by promoter-proximal pausing of RNA polymerase II (Pol II). Phosphorylation of Pol II CTD by positive transcription elongation factor b (P-TEFb) is a necessary precursor event that enables productive transcription elongation. The exact mechanism on how the sequestered P-TEFb is released from the 7SK snRNP complex and recruited to Pol II CTD remains unknown. In this report, we utilize mouse and human models to reveal methylphosphate capping enzyme (MePCE), a core component of the 7SK snRNP complex, as the cognate substrate for Jumonji domain-containing 6 (JMJD6)'s novel proteolytic function. Our evidences consist of a crystal structure of JMJD6 bound to methyl-arginine, enzymatic assays of JMJD6 cleaving MePCE in vivo and in vitro, binding assays, and downstream effects of Jmjd6 knockout and overexpression on Pol II CTD phosphorylation. We propose that JMJD6 assists bromodomain containing 4 (BRD4) to recruit P-TEFb to Pol II CTD by disrupting the 7SK snRNP complex.
Authors
Lee, S; Liu, H; Hill, R; Chen, C; Hong, X; Crawford, F; Kingsley, M; Zhang, Q; Liu, X; Chen, Z; Lengeling, A; Bernt, KM; Marrack, P; Kappler, J; Zhou, Q; Li, C-Y; Xue, Y; Hansen, K; Zhang, G
MLA Citation
Lee, Schuyler, et al. “JMJD6 cleaves MePCE to release positive transcription elongation factor b (P-TEFb) in higher eukaryotes.Elife, vol. 9, Feb. 2020. Pubmed, doi:10.7554/eLife.53930.
URI
https://scholars.duke.edu/individual/pub1431453
PMID
32048991
Source
pubmed
Published In
Elife
Volume
9
Published Date
DOI
10.7554/eLife.53930

Endogenous Retrovirus Activation as a Key Mechanism of Anti-Tumor Immune Response in Radiotherapy.

The generation of DNA double-strand breaks has historically been taught as the mechanism through which radiotherapy kills cancer cells. Recently, radiation-induced cytosolic DNA release and activation of the cGAS/STING pathway, with ensuing induction of interferon secretion and immune activation, have been recognized as important mechanisms for radiation-mediated anti-tumor efficacy. Here we demonstrate that radiation-induced activation of endogenous retroviruses (ERVs) also plays a major role in regulating the anti-tumor immune response during irradiation. Radiation-induced ERV-associated dsRNA transcription and subsequent activation of the innate antiviral MDA5/MAVS/TBK1 pathway led to downstream transcription of interferon-stimulated genes. Additionally, genetic knockout of KAP1, a chromatin modulator responsible for suppressing ERV transcription sites within the genome, enhanced the effect of radiation-induced anti-tumor response in vivo in two different tumor models. This anti-tumor response was immune-mediated and required an intact host immune system. Our findings indicate that radiation-induced ERV-dsRNA expression and subsequent immune response play critical roles in clinical radiotherapy, and manipulation of epigenetic regulators and the dsRNA-sensing innate immunity pathway could be promising targets to enhance the efficacy of radiotherapy and cancer immunotherapy.
Authors
Lee, AK; Pan, D; Bao, X; Hu, M; Li, F; Li, C-Y
MLA Citation
Lee, Andrew K., et al. “Endogenous Retrovirus Activation as a Key Mechanism of Anti-Tumor Immune Response in Radiotherapy.Radiat Res, vol. 193, no. 4, Apr. 2020, pp. 305–17. Pubmed, doi:10.1667/RADE-20-00013.
URI
https://scholars.duke.edu/individual/pub1433317
PMID
32074012
Source
pubmed
Published In
Radiat Res
Volume
193
Published Date
Start Page
305
End Page
317
DOI
10.1667/RADE-20-00013

Necroptosis regulates tumor repopulation after radiotherapy via RIP1/RIP3/MLKL/JNK/IL8 pathway.

BACKGROUND: Tumor cell repopulation after radiotherapy is a major cause for the tumor radioresistance and recurrence. This study aims to investigate the underlying mechanism of tumor repopulation after radiotherapy, with focus on whether and how necroptosis takes part in this process. METHODS: Necroptosis after irradiation were examined in vitro and in vivo. And the growth-promoting effect of necroptotic cells was investigated by chemical inhibitors or shRNA against necroptosis associated proteins and genes in in vitro and in vivo tumor repopulation models. Downstream relevance factors of necroptosis were identified by western blot and chemiluminescent immunoassays. Finally, the immunohistochemistry staining of identified necroptosis association growth stimulation factor was conducted in human colorectal tumor specimens to verify the relationship with clinical outcome. RESULTS: Radiation-induced necroptosis depended on activation of RIP1/RIP3/MLKL pathway, and the evidence in vitro and in vivo demonstrated that the inhibition of necroptosis attenuated growth-stimulating effects of irradiated tumor cells on living tumor reporter cells. The JNK/IL-8 were identified as downstream molecules of pMLKL during necroptosis, and inhibition of JNK, IL-8 or IL-8 receptor significantly reduced tumor repopulation after radiotherapy. Moreover, the high expression of IL-8 was associated with poor clinical prognosis in colorectal cancer patients. CONCLUSIONS: Necroptosis associated tumor repopulation after radiotherapy depended on activation of RIP1/RIP3/MLKL/JNK/IL-8 pathway. This novel pathway provided new insight into understanding the mechanism of tumor radioresistance and repopulation, and MLKL/JNK/IL-8 could be developed as promising targets for blocking tumor repopulation to enhance the efficacy of colorectal cancer radiotherapy.
Authors
Wang, Y; Zhao, M; He, S; Luo, Y; Zhao, Y; Cheng, J; Gong, Y; Xie, J; Wang, Y; Hu, B; Tian, L; Liu, X; Li, C; Huang, Q
MLA Citation
Wang, Yiwei, et al. “Necroptosis regulates tumor repopulation after radiotherapy via RIP1/RIP3/MLKL/JNK/IL8 pathway.J Exp Clin Cancer Res, vol. 38, no. 1, Nov. 2019, p. 461. Pubmed, doi:10.1186/s13046-019-1423-5.
URI
https://scholars.duke.edu/individual/pub1418908
PMID
31706322
Source
pubmed
Published In
J Exp Clin Cancer Res
Volume
38
Published Date
Start Page
461
DOI
10.1186/s13046-019-1423-5

795 K63-Ubiquitin enzyme UBE2N and its variant UBE2V2 play crucial roles in melanoma cell growth and survival

Authors
Dikshit, A; Jin, JY; Hwang, J; Degan, S; Deng, Y; Li, C; Zhang, JY
MLA Citation
Dikshit, A., et al. “795 K63-Ubiquitin enzyme UBE2N and its variant UBE2V2 play crucial roles in melanoma cell growth and survival.” Journal of Investigative Dermatology, vol. 137, no. 5, Elsevier BV, 2017, pp. S137–S137. Crossref, doi:10.1016/j.jid.2017.02.820.
URI
https://scholars.duke.edu/individual/pub1269626
Source
crossref
Published In
Journal of Investigative Dermatology
Volume
137
Published Date
Start Page
S137
End Page
S137
DOI
10.1016/j.jid.2017.02.820

Research Areas:

Caspase 3
Wound Healing