Faculty Bibliography

Adenosine deaminase acting on RNA 1 (ADAR1) contributes to immunotherapy resistance by suppressing interferon signaling. Therapeutic targeting of ADAR1 has not been achieved to date in clinical settings. Here, we discover all-trans retinoic acid (ATRA) promotes ADAR1 protein degradation in cancer. In addition, ATRA induces PD-L1 and combination of ATRA and PD-1 blockade reprograms tumor microenvironments to unleash antitumor immunity, thereby impeding tumor growth. Mechanistically, we identify USP7 as a key regulator for ADAR1 protein stability. ATRA disrupts USP7-ADAR1 interaction and promotes ADAR1 ubiquitination and degradation. ATRA leads to ADAR1 retinoylation, which results in disruption of USP7-ADAR1 complex. Our clinical data shows a positive correlation between USP7 and ADAR1 in various types of cancer. Overall, this study sheds light on control of ADAR1 protein turnover and proposes a mechanism-driven combination therapy using ATRA and PD-1/PD-L1 blockade to convert immunologically "cold" into "hot" tumors, holding potential for clinical translation.

IgE-mediated anaphylaxis is an acute life-threatening systemic reaction to allergens, including certain foods and venoms. Anaphylaxis is triggered when blood-borne allergens activate IgE-bound perivascular mast cells (MCs) throughout the body, causing an extensive systemic release of MC mediators. Through precipitating vasodilatation and vascular leakage, these mediators are believed to trigger a sharp drop in blood pressure in humans and in core body temperature in animals. We report that the IgE/MC-mediated drop in body temperature in mice associated with anaphylaxis also requires the body's thermoregulatory neural circuit. This circuit is activated when granule-borne chymase from MCs is deposited on proximal TRPV1⁺ sensory neurons and stimulates them via protease-activated receptor-1. This triggers the activation of the body's thermoregulatory neural network, which rapidly attenuates brown adipose tissue thermogenesis to cause hypothermia. Mice deficient in either chymase or TRPV1 exhibited limited IgE-mediated anaphylaxis, and, in wild-type mice, anaphylaxis could be recapitulated simply by systemically activating TRPV1⁺ sensory neurons. Thus, in addition to their well-known effects on the vasculature, MC products, especially chymase, promote IgE-mediated anaphylaxis by activating the thermoregulatory neural circuit.

Mitochondria are essential cellular organelles that play critical roles in cancer. Here, as part of the International Cancer Genome Consortium/The Cancer Genome Atlas Pan-Cancer Analysis of Whole Genomes Consortium, which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we performed a multidimensional, integrated characterization of mitochondrial genomes and related RNA sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes and identifies several hypermutated cases. Truncating mutations are markedly enriched in kidney, colorectal and thyroid cancers, suggesting oncogenic effects with the activation of signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA, some of which disrupt therapeutic target genes. Mitochondrial copy number varies greatly within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair and the cell cycle, and shows their connections with clinically actionable genes. Our study lays a foundation for translating mitochondrial biology into clinical applications.