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:

Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer.

Despite its success in achieving the long-term survival of 10-30% of treated individuals, immune therapy is still ineffective for most patients with cancer1,2. Many efforts are therefore underway to identify new approaches that enhance such immune 'checkpoint' therapy3-5 (so called because its aim is to block proteins that inhibit checkpoint signalling pathways in T cells, thereby freeing those immune cells to target cancer cells). Here we show that inhibiting PCSK9-a key protein in the regulation of cholesterol metabolism6-8-can boost the response of tumours to immune checkpoint therapy, through a mechanism that is independent of PCSK9's cholesterol-regulating functions. Deleting the PCSK9 gene in mouse cancer cells substantially attenuates or prevents their growth in mice in a manner that depends on cytotoxic T cells. It also enhances the efficacy of immune therapy that is targeted at the checkpoint protein PD1. Furthermore, clinically approved PCSK9-neutralizing antibodies synergize with anti-PD1 therapy in suppressing tumour growth in mouse models of cancer. Inhibiting PCSK9-either through genetic deletion or using PCSK9 antibodies-increases the expression of major histocompatibility protein class I (MHC I) proteins on the tumour cell surface, promoting robust intratumoral infiltration of cytotoxic T cells. Mechanistically, we find that PCSK9 can disrupt the recycling of MHC I to the cell surface by associating with it physically and promoting its relocation and degradation in the lysosome. Together, these results suggest that inhibiting PCSK9 is a promising way to enhance immune checkpoint therapy for cancer.
Authors
Liu, X; Bao, X; Hu, M; Chang, H; Jiao, M; Cheng, J; Xie, L; Huang, Q; Li, F; Li, C-Y
MLA Citation
Liu, Xinjian, et al. “Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer.Nature, vol. 588, no. 7839, Dec. 2020, pp. 693–98. Pubmed, doi:10.1038/s41586-020-2911-7.
URI
https://scholars.duke.edu/individual/pub1465501
PMID
33177715
Source
pubmed
Published In
Nature
Volume
588
Published Date
Start Page
693
End Page
698
DOI
10.1038/s41586-020-2911-7

Can Glycine Mitigate COVID-19 Associated Tissue Damage and Cytokine Storm?

Authors
Li, C-Y
MLA Citation
Li, Chuan-Yuan. “Can Glycine Mitigate COVID-19 Associated Tissue Damage and Cytokine Storm?Radiat Res, vol. 194, no. 3, Sept. 2020, pp. 199–201. Pubmed, doi:10.1667/RADE-20-00146.1.
URI
https://scholars.duke.edu/individual/pub1461225
PMID
32942307
Source
pubmed
Published In
Radiat Res
Volume
194
Published Date
Start Page
199
End Page
201
DOI
10.1667/RADE-20-00146.1

JMJD5 couples with CDK9 to release the paused RNA polymerase II.

More than 30% of genes in higher eukaryotes are regulated by RNA polymerase II (Pol II) promoter proximal pausing. Pausing is released by the positive transcription elongation factor complex (P-TEFb). However, the exact mechanism by which this occurs and whether phosphorylation of the carboxyl-terminal domain of Pol II is involved in the process remains unknown. We previously reported that JMJD5 could generate tailless nucleosomes at position +1 from transcription start sites (TSS), thus perhaps enable progression of Pol II. Here we find that knockout of JMJD5 leads to accumulation of nucleosomes at position +1. Absence of JMJD5 also results in loss of or lowered transcription of a large number of genes. Interestingly, we found that phosphorylation, by CDK9, of Ser2 within two neighboring heptad repeats in the carboxyl-terminal domain of Pol II, together with phosphorylation of Ser5 within the second repeat, HR-Ser2p (1, 2)-Ser5p (2) for short, allows Pol II to bind JMJD5 via engagement of the N-terminal domain of JMJD5. We suggest that these events bring JMJD5 near the nucleosome at position +1, thus allowing JMJD5 to clip histones on this nucleosome, a phenomenon that may contribute to release of Pol II pausing.
Authors
Liu, H; Ramachandran, S; Fong, N; Phang, T; Lee, S; Parsa, P; Liu, X; Harmacek, L; Danhorn, T; Song, T; Oh, S; Zhang, Q; Chen, Z; Zhang, Q; Tu, T-H; Happoldt, C; O'Conner, B; Janknecht, R; Li, C-Y; Marrack, P; Kappler, J; Leach, S; Zhang, G
MLA Citation
Liu, Haolin, et al. “JMJD5 couples with CDK9 to release the paused RNA polymerase II.Proc Natl Acad Sci U S A, vol. 117, no. 33, Aug. 2020, pp. 19888–95. Pubmed, doi:10.1073/pnas.2005745117.
URI
https://scholars.duke.edu/individual/pub1453830
PMID
32747552
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
117
Published Date
Start Page
19888
End Page
19895
DOI
10.1073/pnas.2005745117

A Gene Mutation Signature Predicting Immunotherapy Benefits in Patients With NSCLC.

INTRODUCTION: Identification of patients who can benefit from immune checkpoint blockade (ICB) therapy is key for improved clinical outcome. Recently, U.S. Food and Drug Administration approved tumor mutational burden (TMB) high (TMB-H or TMB ≥ 10) as a biomarker for pembrolizumab treatment of solid tumors. We intend to test the hypothesis that mutations in select genes may be a better predictor of NSCLC response to ICB therapy than TMB-H. METHODS: We compiled a list of candidate genes that may predict for benefits from ICB treatment by use of data from a recently published cohort of 350 patients with NSCLC. We then evaluated the influences of different mutation signatures in the candidate genes on ICB efficacy. They were also compared with TMB-H. The predictive powers of different mutation signatures were then evaluated in an independent cohort of patients with NSCLC treated with ICB. RESULTS: A compound mutation signature, in which two or more of the 52 candidate genes were mutated, accounted for 145 of 350 patients with NSCLC and was associated with considerable ICB treatment benefits. Specifically, the median duration of overall survival was 36 versus 8 months in NSCLC in those with two or more versus none of the 52 genes mutated. Moreover, those patients with the compound mutation signature but had low TMB (<10) achieved significant overall survival benefits when compared with those without the signature but had TMB-H (≥10). Finally, in an independent cohort of 156 patients with ICB-treated NSCLC, the median duration of progression-free survival was 8.3 months versus 3.5 months in those with the compound mutation signature versus those with none mutated in the 52 genes. CONCLUSIONS: A genetic signature with mutations in at least two of 52 candidate genes was superior than TMB-H in predicting clinical benefits for ICB therapy in patients with NSCLC.
Authors
Pan, D; Hu, AY; Antonia, SJ; Li, C-Y
MLA Citation
Pan, Dong, et al. “A Gene Mutation Signature Predicting Immunotherapy Benefits in Patients With NSCLC.J Thorac Oncol, vol. 16, no. 3, Mar. 2021, pp. 419–27. Pubmed, doi:10.1016/j.jtho.2020.11.021.
URI
https://scholars.duke.edu/individual/pub1468788
PMID
33307194
Source
pubmed
Published In
J Thorac Oncol
Volume
16
Published Date
Start Page
419
End Page
427
DOI
10.1016/j.jtho.2020.11.021

ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage and cGAS/STING activation.

Novel approaches are needed to boost the efficacy of immune checkpoint blockade (ICB) therapy. Ataxia telangiectasia mutated (ATM) protein plays a central role in sensing DNA double-stranded breaks (DSBs) and coordinating their repair. Recent data indicated that ATM might be a promising target to enhance ICB therapy. However, the molecular mechanism involved has not been clearly elucidated. Here, we show that ATM inhibition could potentiate ICB therapy by promoting cytoplasmic leakage of mitochondrial DNA (mtDNA) and activation of the cGAS/STING pathway. We show that genetic depletion of ATM in murine cancer cells delayed tumor growth in syngeneic mouse hosts in a T cell-dependent manner. Furthermore, chemical inhibition of ATM potentiated anti-PD-1 therapy of mouse tumors. ATM inhibition potently activated the cGAS/STING pathway and enhanced lymphocyte infiltration into the tumor microenvironment by downregulating mitochondrial transcription factor A (TFAM), which led to mtDNA leakage into the cytoplasm. Moreover, our analysis of data from a large patient cohort indicated that ATM mutations, especially nonsense mutations, predicted for clinical benefits of ICB therapy. Our study therefore provides strong evidence that ATM may serve as both a therapeutic target and a biomarker to enable ICB therapy.
Authors
Hu, M; Zhou, M; Bao, X; Pan, D; Jiao, M; Liu, X; Li, F; Li, C-Y
MLA Citation
Hu, Mengjie, et al. “ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage and cGAS/STING activation.J Clin Invest, vol. 131, no. 3, Feb. 2021. Pubmed, doi:10.1172/JCI139333.
URI
https://scholars.duke.edu/individual/pub1468787
PMID
33290271
Source
pubmed
Published In
J Clin Invest
Volume
131
Published Date
DOI
10.1172/JCI139333

Research Areas:

Caspase 3
Wound Healing