Branched-Chain Amino Acid Accumulation Fuels the Senescence-Associated Secretory Phenotype.

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2023-11

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Abstract

The essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs' full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence-associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation-related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation of the catabolic enzyme BCAA transaminase 1 during onset of cellular senescence, leading to highly elevated intracellular BCAA levels in senescent cells. This, in turn, activates the mammalian target of rapamycin complex 1 (mTORC1) to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous BCAA regulators are involved in the induction of cellular senescence and age-related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during aging. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse senescence model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age-related and inflammatory diseases.

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10.1002/advs.202303489

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Liang, Yaosi, Christopher Pan, Tao Yin, Lu Wang, Xia Gao, Ergang Wang, Holly Quang, De Huang, et al. (2023). Branched-Chain Amino Acid Accumulation Fuels the Senescence-Associated Secretory Phenotype. Advanced science (Weinheim, Baden-Wurttemberg, Germany). p. e2303489. 10.1002/advs.202303489 Retrieved from https://hdl.handle.net/10161/29454.

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Scholars@Duke

Li

Qi-Jing Li

Adjunct Associate Professor in the Department of Immunology

Recent clinical success in cancer immunotherapy, including immune checkpoint blockades and chimeric antigen receptor T cells, have settled a long-debated question in the field: whether tumors can be recognized and eliminated by our own immune system, specifically, the T lymphocyte. Meanwhile, current limitations of these advanced treatments pinpoint fundamental knowledge deficits in basic T cell biology, especially in the context of tumor-carrying patients. Aiming to develop new immunotherapies against cancers, and interconnected with clinical trials executed by clinician collaborators and immunogenomic tools developed in house, my research program rests on three pillars – the T cell, the Tumor Microenvironment, and Immunotherapy.

We regard the tumor as an acquired immunosuppressive organ. By this scientific precept, we study how tumors inhibit T cell-mediated immunity both locally and systemically. Our early TCR repertoire profiling of gastric tumors and tumor-free patient mucosa revealed the correlation between tissue resident T cell diversity and patient survival. Our recent single cell RNA sequencing study depicted complex pathways to develop T cell memory intratumorally. Currently, aided by bioinformatics and animal models, we are actively dissecting signaling pathways, transcription regulatory networks, and epigenetic programs governing T cell differentiation in the tumor microenvironment. Moving beyond the local microenvironment, our previous studies also demonstrated that tumors remotely modulate T cell antigen-priming events in the spleen. This ongoing in-depth investigation has gradually unveiled the profound impact of this “tele-education”: established tumors hijack hematopoiesis to protect themselves against T cell surveillance. The next step is to identify those evil envoys sent out by tumors carrying signals for systemic immune suppression.

The expanding boundary of T cell biology is the frontier of cancer immunotherapy. The contrast between the unprecedented success of T cell-based therapies for blood malignancies and their repeated failures against solid tumors vividly highlights our prevalent challenges: to understand how T cells can infiltrate tumors; how infiltrated T cells can resist microenvironmental suppression; and how activated T cells can form persistent memory to restrict tumor development and metastasis. During the last decade, my laboratory invested heavily in the microRNA (miRNA) field, deeming miRNAs a unique tool for T cell biology discovery. Identifying miRNA functions and targets is our path to discovering novel proteins, or novel functions of known proteins, in T cell regulation. Expression profiling and functional screening in the lab have produced many candidates to make T cells smarter and stronger. Due to their size, these miRNA candidates can be easily combined with targeting moieties to armor T cells, and we have incorporated these small weaponries, and introduced genomic manipulations on their downstream targets, into CAR-T cells for pre-clinical studies. Indeed, some of them greatly enhance CAR-T’s anti-tumor function. As a general principle, we believe that it is necessary to empower transferred CAR T or TCR-T cells with enhanced functionality against solid tumors. We also believe the T cell is a perfect platform to integrate genomic engineering for combinatory cancer therapy. Currently, we are actively involved in three such armored CAR-T or TCR-T trials for various solid tumor treatments.  

Accompanying these trials, and other immunotherapies carried out by colleagues on campus and world-wide, we design and execute comprehensive immune monitoring procedures to rationalize successes and failures. Clinical observations are smoothly deconstructed into basic but intriguing T cell questions for us to answer, and answers generated on the bench directly inform T cell designs in future trials. This is our closed circle of research and day-to-day operation.

Yao

Tso-Pang Yao

Professor of Pharmacology and Cancer Biology

My laboratory studies the regulatory functions of protein acetylation in cell signaling and human disease. We focus on a class of protein deacetylases, HDACs, which we have discovered versatile functions beyond gene transcription. We wish to use knowledge of HDAC biology to develop smart and rational clinical strategies for HDAC inhibitors, a growing class of compounds that show potent anti-tumor and other clinically relevant activities. Currently, there two major research major areas in the laboratory: aging/age-related disease, and mitochondrial biology/cancer metabolism. 

(1) Quality control (QC) autophagy in aging and neurodegenerative disease. The accumulation of damaged proteins and mitochondria is prominently linked to aging and age-associated disease, including neurodegeneration, metabolic disorders and cancer. Autophagy has emerged as specialized degradation machinery for the disposal of damaged protein aggregates and mitochondria, two common denominators in neurodegenerative diseases. We have discovered that this form of quality control (QC) autophagy is controlled by a ubiquitin-binding deacetylase, HDAC6.  Using both mouse and cell models, we are investigating how HDAC6 enforces QC autophagy and its importance in neurodegenerative disease and metabolic disorders. The potential of HDAC6 as a therapeutic target is being actively pursued.

(2) HDAC in mitochondria function and quality control. Acetyl-CoA is the donor of acetyl group for protein acetylation and numerous metabolic reactions. Remarkably, many mitochondrial enzymes and proteins are subject to acetylation. We are interested in characterizing the roles of HDAC in mitochondrial adaptation to changing metabolic demands and elucidating the intimate relationship between metabolism and protein acetylation. 

(3) HDAC, skeletal muscle remodeling, regeneration and neuromuscular disease. Skeletal muscle undergoes active remodeling in response to change in neural inputs or damage. Loss in neural input causes dramatic muscle dysfunction and disease, such as ALS. We have discovered that neural activity controls muscle phenotype through HDAC4, whose activity becomes deregulated in ALS patients. We have characterized this novel HDAC4-dependent signaling pathway and are evaluating modulators of this pathway for potential clinical utility in motor neuron disease.


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