Meeting the Editorial Board Member of TLCR: Dr. Daolin Tang

Posted On 2024-04-10 17:02:05


Daolin Tang1, Jin Ye Yeo2

1Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA; 2TLCR Editorial Office, AME Publishing Company

Correspondence to: Jin Ye Yeo. TLCR Editorial Office, AME Publishing Company. Email: editors@TLCR.org


Expert Introduction

Dr. Daolin Tang (Figure 1) is a professor in the Department of Surgery at the University of Texas Southwestern Medical Center, where he serves as the director of the Center for DAMP Biology. He is a biologist engaged in cutting-edge research focused on investigating the regulation and function of damage-associated molecular pattern molecules (DAMPs) in cell death and immunity. Specifically, he has made contributions to the field by elucidating novel pathological roles for HMGB1 in infection, sterile inflammation, and cancer. Additionally, his research has uncovered new regulators of autophagy, ferroptosis, pyroptosis, and alkaliptosis in cancer therapy as well as bacterial infection.

Figure 1 Dr. Daolin Tang

Dr. Tang's findings have been published in esteemed scientific journals, such as Gastroenterology, Gut, Hepatology, Science Translational Medicine, Developmental Cell, Cell Metabolism, Nature Microbiology, Immunity, Cell Host & Microbe, Autophagy, Nature Cell Biology, and Nature Immunology.

In recognition of his expertise, he has been appointed as a member of the International Cell Death Nomenclature Committee, contributing to the establishment of standardized research guidelines in the field of cell death and autophagy. Furthermore, his scholarly contributions have garnered significant recognition, as evidenced by an H index of 117 and designation as one of Clarivate’s Highly Cited Researchers worldwide.


Interview

TLCR: What drove you into the field of sepsis and cell death?

Dr. Tang: Sepsis, a multifaceted syndrome marked by a dysregulated host response to infection, represents a significant global health challenge, with mortality rates ranging from 15% to 30% or higher. My journey into sepsis research began following my graduation from Norman Bethune Medical University (now part of Jilin University) in China. It was during my time there that my passion for basic medical research, particularly in unraveling the molecular mechanisms underlying inflammatory responses, was ignited.

Recognizing the intricate interplay between sepsis and the inflammatory cascade, I returned to my hometown of Hunan Province in China and took up a teaching position within the Department of Pathophysiology at Xiangya Medical School of Central South University. Renowned for its robust exploration of sepsis mechanisms in China, the department provided an ideal environment for my scholarly pursuits. Under the guidance of Dr. Xianzhong Xiao, I embarked on my doctoral journey, focusing specifically on elucidating the role of high mobility group box 1 (HMGB1) release modulated by oxidative stress and heat shock proteins in the pathogenesis of sepsis (1-3).

Seeking to expand my research horizons, I endeavored to pursue opportunities in the United States, home to world-renowned sepsis research laboratories, particularly within surgical departments. Fortunately, I secured a prestigious postdoctoral position in Dr. Michael Lotze's lab at the Department of Surgery, University of Pittsburgh. Dr. Lotze's expertise in HMGB1 and tumor immunity research offered a fertile ground for my exploration into novel aspects of HMGB1 involvement, particularly in autophagy and cell death (4,5).

Upon completing my postdoctoral training, I transitioned to a faculty position within the Department of Surgery at the University of Pittsburgh. Here, my research interests expanded into two primary areas. I continued my investigation into sepsis mechanisms (6-18), fostering collaborative partnerships with esteemed researchers, such as Drs. Timothy Billiar and Haichao Wang at the University of Pittsburgh and Feinstein Institutes for Medical Research, respectively. Their groundbreaking findings on the extracellular role of HMGB1 in sterile inflammation and bacterial infection significantly influenced the trajectory of my research endeavors (19,20). Furthermore, I have delved into investigating novel forms of cell death, such as ferroptosis (21-39) and alkaliptosis (40-43), and their interplay with autophagy through collaboration with Drs. Guido Kroemer (University of Paris Descartes) and Daniel Klionsky (University of Michigan). Our aim is to deepen our understanding of cancer biology while identifying potential therapeutic targets.

TLCR: What made you direct your research focus on damage-associated molecular pattern molecules (DAMPs)?

Dr. Tang: DAMPs, or Damage-Associated Molecular Patterns, are endogenous molecules released by stressed, damaged, or dying cells in response to cellular injury or stress. They serve as danger signals that alert the immune system to tissue damage and initiate inflammatory responses. Dysregulated DAMP signaling has been implicated in various inflammatory and autoimmune diseases, making them important targets for therapeutic intervention. DAMPs can originate from various cellular compartments, including the cytoplasm, nucleus, mitochondria, and extracellular matrix. Notably, HMGB1 stands as one of the most extensively studied DAMPs, playing a pivotal role in diseases associated with cell death and tissue damage (44). As discussed, my PhD thesis and postdoctoral training focused on HMGB1 in sepsis and autophagy. Furthermore, in addition to HMGB1, my laboratory is currently involved in identifying new DAMPs under different stress conditions.

TLCR: Would you like to give us a general picture of the publication area of DAMPs?

Dr. Tang: My contributions to the DAMP field can be divided into three main areas. Firstly, under the guidance of Dr. Michael Lotze and in collaboration with Drs. Rui Kang and Herbert Zeh, we elucidated the significant role of HMGB1 in autophagy. In response to starvation or oxidative stress, HMGB1 translocates to the cytosol and is subsequently released into the extracellular space. We demonstrated that cytosolic HMGB1 binds beclin 1 (BECN1, also known as Atg6 in yeast) to initiate autophagosome formation (45). Interestingly, we found that reduced extracellular HMGB1, rather than oxidized HMGB1, interacts with advanced glycosylation end-product specific receptor (AGER, also known as RAGE), activating phosphatidylinositol 3-phosphate kinase (PI3K) and promoting autophagosome formation (46,47). Additionally, our research revealed that nuclear HMGB1 affects heat shock protein family B (small) member 1 (HSPB1, also known as HSP25 or HSP27) expression, thereby modulating cytoskeletal dynamics to regulate autophagy and mitophagy (48). These findings establish the HMGB1-dependent autophagy theory.

Secondly, we identified the autophagy receptor protein sequestosome 1 (SQSTM1) as a novel DAMP and immune mediator in sepsis and pancreatitis (9,49). SQSTM1 can be released by lipopolysaccharide or passively during pyroptosis, an inflammatory cell death process in macrophages. Once released, SQSTM1 binds to the insulin receptor (INSR) in macrophages, triggering an inflammatory response. Furthermore, extracellular SQSTM1 binds to AGER on pancreatic acinar cells, inducing acyl-CoA synthetase long-chain family member 4 (ACSL4) expression and increasing sensitivity to ferroptosis. These findings suggest that extracellular SQSTM1 could serve as a therapeutic target in infections and tissue damage.

Thirdly, we discovered that decorin (DCN), a small leucine-rich proteoglycan that is found in the extracellular matrix of various tissues, is a specific DAMP that distinguishes ferroptosis from other cell death modalities (50). Ferroptosis is an iron-dependent oxidative death characterized by uncontrolled lipid peroxidation (50). Our research demonstrated that DCN is an early and specific DAMP in ferroptosis, providing a biomarker to monitor ferroptotic responses. In addition to these major contributions, our research has also explored the functions of other DAMPs, including but not limited to histones (52, 53) and transcription factor A, mitochondrial (TFAM) (54).

TLCR: In your research works, you have elucidated novel pathological roles for HMGB1 in infection, sterile inflammation, and cancer. What does this entail, for both the medical professionals and the laymen?

Dr. Tang: Our research, along with that of other distinguished scientists, has revealed that HMGB1 is a multifaceted protein with location- and redox-dependent roles in various pathological conditions, including infection, sterile inflammation, and cancer. For instance, intracellular HMGB1 may generally play an oncogenic role in promoting tumor growth. We discovered that conditional knockout of Hmgb1 in the liver limits diethylnitrosamine-induced liver tumorigenesis by regulating the Hippo pathway (55). On the contrary, our research revealed that conditional knockout of Hmgb1 in the pancreas accelerates KrasG12D-driven tumorigenesis by releasing histones, which subsequently induces an inflammatory response (56, 57). Moreover, reduced HMGB1 exhibits pro-autophagy activity, while oxidized HMGB1 displays pro-apoptotic activity in cancer cells (47). Thus, the same protein can exhibit many different facets. It is imperative that we carefully examine the context-dependent role of HMGB1 in human disease (44).

Nevertheless, we also need to develop specific HMGB1-related drugs to inhibit or activate its location- or modification-dependent roles. This research has significant implications for medical professionals as it sheds light on the complex role of HMGB1 in disease pathogenesis, informing potential therapeutic strategies. For the general public, understanding the diverse functions of HMGB1 underscores the complexity of disease processes and the importance of targeted therapeutic approaches in combating various health conditions.

TLCR: In your multidisciplinary research team (Tang Lab), what were some of the most challenging issues you tackled in the field of cancer biology and lethal infections? How did you and your team overcome these issues?

Dr. Tang: One of the most formidable challenges we encountered was addressing reproducibility issues in biomedical experiments. These issues can stem from various factors, including:

1) Experimental design: Poorly designed experiments, such as inadequate sample sizes, lack of appropriate controls, and biased selection of experimental conditions, can lead to irreproducible results. To address this, we emphasized clear and well-defined experimental protocols to ensure reproducibility.

2) Variability in biological systems: Biological systems are inherently variable due to factors like genetic background, age, sex, and environmental conditions. To mitigate this variability, we standardized experimental conditions and carefully considered biological variability in our analyses.

3) Technical variability: Variability in experimental techniques, equipment, reagents, cell lines, and laboratory conditions can impact reproducibility. We implemented protocols for standardization, equipment calibration, and rigorous quality control measures to minimize technical variability.

4) Researcher bias: Unconscious biases, preconceptions, and subjective interpretations of data can influence experimental outcomes and contribute to irreproducibility. To mitigate researcher bias, we implemented double-blind experimental designs and encouraged independent validation by multiple researchers.

By addressing these challenges head-on and implementing robust methodologies and quality control measures, we were able to enhance the reproducibility and reliability of our research findings in the fields of cancer biology and lethal infections.

TLCR: Other than being a researcher with impressive scholarly contributions, as evidenced by your H index of 117, you are also a member of the International Cell Death Nomenclature Committee. What keeps you motivated and committed to your line of work?

Dr. Tang: My career path was significantly shaped by my postdoctoral mentor, Dr. Michael Lotze. His perpetual energy, ability to multitask, and consistently positive demeanor served as a profound source of inspiration for me. Witnessing his actions and adopting his qualities encouraged me to actively collaborate with peers and immerse myself in various scientific endeavors. These collaborative efforts have resulted in broader impacts in our field. For example, I recently led the development of two international guidelines for ferroptosis research, published in Nature Cell Biology (58) and Autophagy (59). It's worth mentioning that Dr. Lotze, who is an avid runner, introduced me to marathons and trail running, which expanded my appreciation for nature.

TLCR: How has your experience been as an Editorial Board Member of TLCR?

Dr. Tang: As an Editorial Board Member, my experience has been incredibly rewarding and fulfilling. It has afforded me the opportunity to contribute to the advancement of scientific knowledge by evaluating and shaping the quality of research publications in my field. Serving on the editorial board has enabled me to stay abreast of the latest developments in my area of expertise and engage with cutting-edge research from around the world. Moreover, this role has allowed me to develop and refine critical skills, such as manuscript evaluation, constructive feedback delivery, and decision-making. These skills not only benefit my own research endeavors but also empower me to mentor and guide emerging researchers in the field.

TLCR: As an Editorial Board Member of TLCR, what are your expectations for TLCR?

Dr. Tang: I expect TLCR to uphold scientific integrity, excellence, and innovation in lung cancer research. TLCR should serve as a leading platform for disseminating cutting-edge research findings and translational advancements aimed at improving prevention, diagnosis, and treatment. Specifically, TLCR should: 1) Foster collaboration among researchers, clinicians, and industry professionals. 2) Emphasize translational research to bridge basic science discoveries with clinical applications. 3) Maintain rigorous peer review to ensure high-quality publications. 4) Support early career researchers through mentorship and networking opportunities.


Reference

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