Parangi, S. | Search bioRxiv

bioRxiv2025

Immune-parenchymal multicellular niches are shared across distinct thyroid autoimmune diseases

Thyroid hormone, produced in the thyroid gland, regulates metabolism, development, and cardiac function. The thyroid is susceptible to autoimmune attack by both cellular and humoral immunity exemplified by Hashimotos thyroiditis (HT) and Graves Disease (GD), respectively. In HT, immune-mediated destruction impairs thyroid hormone production, while in GD, stimulating autoantibodies promote over-production. Here, we generated a multi-modal atlas of 604,076 human thyroid and blood cells from HT, GD, and control patients. We found that, despite markedly different clinical presentations and distinct antigenic triggers, HT and GD exhibit convergent cellular dynamics resulting in a shared continuum of immune infiltration. Along this continuum, a key feature is a thyrocyte niche containing CD8+ T cells that may segregate pathogenic T cells from regions with preserved thyroid hormone production. These findings of a shared disease continuum characterized by spatially defined immune niches provide a new framework for understanding tissue homeostasis in human autoimmune disease.

immunology↗

bioRxiv2022

Effectors enabling adaptation to mitochondrial complex I loss in Hurthle cell carcinoma

Oncocytic (Hurthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here, we utilize RNA-seq and metabolomics to identify candidate molecular effectors activated by these genetic drivers. We find glutathione biosynthesis, amino acid metabolism, mitochondrial unfolded protein response, and lipid peroxide scavenging, a safeguard against ferroptosis, to be increased in HCC. A CRISPR-Cas9 knockout screen in a new HCC model reveals which pathways are key for fitness, and highlights loss of GPX4, a defense against ferroptosis, as a strong liability. Rescuing complex I redox activity with the yeast NADH dehydrogenase (NDI1) in HCC cells diminishes ferroptosis sensitivity, while inhibiting complex I in normal thyroid cells augments ferroptosis induction. Our work demonstrates unmitigated lipid peroxide stress to be an HCC vulnerability that is mechanistically coupled to the genetic loss of mitochondrial complex I activity. SignificanceOncocytic (Hurthle cell) carcinoma of the thyroid (HCC) is a unique tumor with a remarkable accumulation of mitochondria. HCC harbors unique genetic alterations, including mitochondrial DNA (mtDNA) mutations in complex I genes and widespread loss-of-heterozygosity in the nuclear DNA. With less favorable clinical outcomes, new therapies for HCC are needed, especially since these tumors show intrinsic resistance to radioactive iodine, which is one of the main treatments for metastatic well-differentiated thyroid cancer. An absence of authentic HCC cell lines and animal models has hindered the mechanistic understanding of this disease and slowed therapeutic progress. In this study, we describe the transcriptomic and metabolomic landscape of HCC and present new HCC models that recapitulate key mtDNA and nuclear DNA alterations. A targeted CRISPR-Cas9 knockout screen in an HCC cell line highlights the molecular programs nominated by our -omics profiling that are required for cell fitness. This screen suggests that lipid peroxide scavenging, a defense system against an iron-dependent form of cell death known as ferroptosis, is a vulnerability in HCC that is coupled to complex I loss, and that targeting this pathway may help patients with HCC.

cancer biology↗