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

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Duke Regeneration Center

Regeneration Next Initiative
School of Medicine

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
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:

SETDB1 Restrains Endogenous Retrovirus Expression and Antitumor Immunity during Radiotherapy.

The type I interferon response plays a pivotal role in promoting antitumor immune activity in response to radiotherapy. The identification of approaches to boost the radiation-induced type I interferon response could help improve the efficacy of radiotherapy. Here we show that the histone methyltransferase SETDB1 is a potent suppressor of radiation-induced endogenous retrovirus expression. SETDB1 inhibition significantly enhanced the efficacy of radiotherapy by promoting radiation-induced viral mimicry to upregulate type I interferons. SETDB1 expression correlated with radiotherapy efficacy in human non-small cell carcinoma and melanoma patients. In a murine tumor model, genetic deletion of Setdb1 significantly enhanced radiotherapy efficacy, and Setdb1-deficient tumors had enhanced intratumoral lymphocyte infiltration, an observation confirmed in human cancer samples. Setdb1 deficiency led to increased basal and radiation-induced endogenous retrovirus (ERV) expression, enhanced MDA5/MAVS signaling, and upregulated type I interferons, which were essential for SETDB1 deficiency-induced radiosensitization. Taken together, these data suggest that inhibition of SETDB1 is a promising approach to enhance cancer radiotherapy efficacy by promoting radiation-induced viral mimicry and antitumor immunity through ERV induction. SIGNIFICANCE: The identification of the SETDB1-mediated suppression of radiotherapy-induced viral mimicry reveals SETDB1 inhibition as a potential approach to sensitize tumors to radiotherapy by enhancing the type I interferon response.
Authors
Pan, D; Bao, X; Hu, M; Jiao, M; Li, F; Li, C-Y
MLA Citation
Pan, Dong, et al. “SETDB1 Restrains Endogenous Retrovirus Expression and Antitumor Immunity during Radiotherapy.Cancer Res, vol. 82, no. 15, Aug. 2022, pp. 2748–60. Pubmed, doi:10.1158/0008-5472.CAN-21-3523.
URI
https://scholars.duke.edu/individual/pub1524212
PMID
35648422
Source
pubmed
Published In
Cancer Res
Volume
82
Published Date
Start Page
2748
End Page
2760
DOI
10.1158/0008-5472.CAN-21-3523

Inhibition of ALG3 stimulates cancer cell immunogenic ferroptosis to potentiate immunotherapy.

Immune checkpoint blockade therapy has drastically improved the prognosis of certain advanced-stage cancers. However, low response rates and immune-related adverse events remain important limitations. Here, we report that inhibiting ALG3, an a-1,3-mannosyltransferase involved in protein glycosylation in the endoplasmic reticulum (ER), can boost the response of tumors to immune checkpoint blockade therapy. Deleting N-linked glycosylation gene ALG3 in mouse cancer cells substantially attenuates their growth in mice in a manner depending on cytotoxic T cells. Furthermore, ALG3 inhibition or N-linked glycosylation inhibitor tunicamycin treatment synergizes with anti-PD1 therapy in suppressing tumor growth in mouse models of cancer. Mechanistically, we found that inhibiting ALG3 induced deficiencies of post-translational N-linked glycosylation modification and led to excessive lipid accumulation through sterol-regulated element-binding protein (SREBP1)-dependent lipogenesis in cancer cells. N-linked glycosylation deficiency-mediated lipid hyperperoxidation induced immunogenic ferroptosis of cancer cells and promoted a pro-inflammatory microenvironment, which boosted anti-tumor immune responses. In human subjects with cancer, elevated levels of ALG3 expression in tumor tissues are associated with poor patient survival. Taken together, we reveal an unappreciated role of ALG3 in regulating tumor immunogenicity and propose a potential therapeutic strategy for enhancing cancer immunotherapy.
Authors
Liu, P; Lin, C; Liu, Z; Zhu, C; Lin, Z; Xu, D; Chen, J; Huang, Q; Li, C-Y; Hou, L; Pan, J-A; Liu, X
MLA Citation
Liu, Pei, et al. “Inhibition of ALG3 stimulates cancer cell immunogenic ferroptosis to potentiate immunotherapy.Cell Mol Life Sci, vol. 79, no. 7, June 2022, p. 352. Pubmed, doi:10.1007/s00018-022-04365-4.
URI
https://scholars.duke.edu/individual/pub1524211
PMID
35676564
Source
pubmed
Published In
Cell Mol Life Sci
Volume
79
Published Date
Start Page
352
DOI
10.1007/s00018-022-04365-4

SET8 Inhibition Potentiates Radiotherapy by Suppressing DNA Damage Repair in Carcinomas.

Objective: SET8 is a member of the SET domain-containing family and the only known lysine methyltransferase (KMT) that monomethylates lysine 20 of histone H4 (H4K20me1). SET8 has been implicated in many essential cellular processes, including cell cycle regulation, DNA replication, DNA damage response, and carcinogenesis. There is no conclusive evidence, however, regarding the effect of SET8 on radiotherapy. In the current study we determined the efficacy of SET8 inhibition on radiotherapy of tumors and the underlying mechanism. Methods: First, we explored the radiotherapy benefit of the SET8 expression signature by analyzing clinical data. Then, we measured a series of biological endpoints, including the xenograft tumor growth in mice and apoptosis, frequency of micronuclei, and foci of 53BP1 and γ-H2AX in cells to detect the SET8 effects on radiosensitivity. RNA sequencing and subsequent experiments were exploited to verify the mechanism underlying the SET8 effects on radiotherapy. Results: Low expression of SET8 predicted a better benefit to radiotherapy in lung adenocarcinoma (LUAD) and invasive breast carcinoma (BRCA) patients. Furthermore, genetic deletion of SET8 significantly enhanced radiation treatment efficacy in a murine tumor model, and A549 and MCF7 cells; SET8 overexpression decreased the radiosensitivity. SET8 inhibition induced more apoptosis, the frequency of micronuclei, and blocked the kinetics process of DNA damage repair as 53BP1 and γ-H2AX foci remained in cells. Moreover, RNF8 was positively correlated with the SET8 impact on DNA damage repair. Conclusion: Our results demonstrated that SET8 inhibition enhanced radiosensitivity by suppressing DNA damage repair, thus suggesting that SET8 potentiated radiotherapy of carcinomas. As new inhibitors of SET8 are synthesized and tested in preclinical and clinical settings, combining SET8 inhibitors with radiation warrants consideration for precise radiotherapy.
Authors
Pan, D; Du, YR; Li, R; Shen, AH; Liu, XD; Li, CY; Hu, BR
MLA Citation
Pan, Dong, et al. “SET8 Inhibition Potentiates Radiotherapy by Suppressing DNA Damage Repair in Carcinomas.Biomed Environ Sci, vol. 35, no. 3, Mar. 2022, pp. 194–205. Pubmed, doi:10.3967/bes2022.028.
URI
https://scholars.duke.edu/individual/pub1513632
PMID
35317899
Source
pubmed
Published In
Biomed Environ Sci
Volume
35
Published Date
Start Page
194
End Page
205
DOI
10.3967/bes2022.028

Targeting Glycolysis in Alloreactive T Cells to Prevent Acute Graft-Versus-Host Disease While Preserving Graft-Versus-Leukemia Effect.

Alloreactive donor T cells undergo extensive metabolic reprogramming to become activated and induce graft-versus-host disease (GVHD) upon alloantigen encounter. It is generally thought that glycolysis, which promotes T cell growth and clonal expansion, is employed in this process. However, conflicting data have been reported regarding the requirement of glycolysis to induce T cell-mediated GVHD due to the lack of T cell-specific treatments using glycolysis inhibitors. Importantly, previous studies have not evaluated whether graft-versus-leukemia (GVL) activity is preserved in donor T cells deficient for glycolysis. As a critical component affecting the clinical outcome, it is necessary to assess the anti-tumor activity following treatment with metabolic modulators in preclinical models. In the present study, we utilized T cells selectively deficient for glucose transporter 1 (Glut1T-KO), to examine the role of glycolysis exclusively in alloreactive T cells without off-targeting effects from antigen presenting cells and other cell types that are dependent on glycolysis. We demonstrated that transfer of Glut1T-KO T cells significantly improved acute GVHD outcomes through increased apoptotic rates, impaired expansion, and decreased proinflammatory cytokine production. In addition to impaired GVHD development, donor Glut1T-KO T cells mediated sufficient GVL activity to protect recipients from tumor development. A clinically relevant approach using donor T cells treated with a small molecule inhibitor of glycolysis, 2-Deoxy-D-glucose ex vivo, further demonstrated protection from tumor development. These findings indicate that treatment with glycolysis inhibitors prior to transplantation selectively eliminates alloreactive T cells, but spares non-alloreactive T cells including those that protect against tumor growth. The present study has established a definitive role for glycolysis in acute GVHD and demonstrated that acute GVHD can be selectively prevented through targeting glycolysis.
Authors
Huang, Y; Zou, Y; Jiao, Y; Shi, P; Nie, X; Huang, W; Xiong, C; Choi, M; Huang, C; Macintyre, AN; Nichols, A; Li, F; Li, C-Y; MacIver, NJ; Cardona, DM; Brennan, TV; Li, Z; Chao, NJ; Rathmell, JC; Chen, BJ
MLA Citation
Huang, Ying, et al. “Targeting Glycolysis in Alloreactive T Cells to Prevent Acute Graft-Versus-Host Disease While Preserving Graft-Versus-Leukemia Effect.Front Immunol, vol. 13, 2022, p. 751296. Pubmed, doi:10.3389/fimmu.2022.751296.
URI
https://scholars.duke.edu/individual/pub1512762
PMID
35296079
Source
pubmed
Published In
Frontiers in Immunology
Volume
13
Published Date
Start Page
751296
DOI
10.3389/fimmu.2022.751296

Delivery of plasmid DNA through intratumoral infusion and electroporation

We investigated DNA transport in the interstitial spaceand across cell membrane facilitated by intratumoral infusionand in vivo electroporation, respectively. In the study, a ratfibrosarcoma was perfused ex vivo, and apparent hydraulicconductivity (Kaap) was quantified under different perfusionconditions. In addition, three plasmid DNA vectors wereinfused into solid tumors. Immediately after infusion, tumorswere treated with or without electric pulses. Gene expressionand tumor growth delay were determined at different timepoints after electroporation. We found that K m was verysensitive to the perfusion pressure, presumably due toperfusion-induced tissue deformation. Treatment of tumorswith electric pulse facilitated gene expression in vivo. Thegrowth of tumors treated with plasmid DNA encodinginterleukin 12 (IL-12) and electric pulses was slower thanthose treated with IL-12 or electric pulses alone. These datasuggest that gene delivery in solid tumors could be improvedsignificantly through combination of intratumoral infusion andin vivo electroporation.
Authors
Yuan, F; Zaharoff, D; Zhang, XY; Lohr, F; Dewhirst, MW; Li, CY
MLA Citation
Yuan, F., et al. “Delivery of plasmid DNA through intratumoral infusion and electroporation.” Asme International Mechanical Engineering Congress and Exposition, Proceedings (Imece), vol. 2000-F, 2000, pp. 125–28. Scopus, doi:10.1115/IMECE2000-2231.
URI
https://scholars.duke.edu/individual/pub1502506
Source
scopus
Published In
Asme International Mechanical Engineering Congress and Exposition, Proceedings (Imece)
Volume
2000-F
Published Date
Start Page
125
End Page
128
DOI
10.1115/IMECE2000-2231

Research Areas:

Caspase 3
Wound Healing