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bioRxiv2023

New insights into iodide metabolism based on preclinical models: impact on radiotherapy efficacy and protection against radioactive iodine exposure.

BackgroundThe main basic aspects of the regulation of thyroid metabolism by iodine are known, but given the complexity of the mechanisms involved, further analyzes in living animals are still required. Here, we provided new insights into iodine physiology but also into the optimization of radiotherapy with iodine, as well as effective countermeasures in the case of an exposure to radioactive iodine. MethodsWe performed Single Photon Emission Computed Tomography (SPECT) coupled to an X-ray scanner to record radiotracers in living mice and rats. Our imaging system was similar to that routinely used in nuclear medicine but was specifically designed for studies with small animals. Different modalities of administration of radioactive iodine or its radioactive analogues combined with a low or high iodine diet have been studied in pregnant, lactating and control animals. To optimize countermeasures against acute or chronic iodine exposure, the protective effects of potassium iodide (KI) administration protocols were analyzed. Perchlorate was administered to study the iodine metabolism in the kidney and stomach. ResultsOur results showed how the various organs capable of iodine uptake adapt to an iodine-deficient diet. Indeed, the uptake capacity of the thyroid gland, but also that of the salivary glands was significantly increased on a low iodine diet. In contrast, the iodine uptake capacity of the thyroid and lactating mammary glands was reduced on an iodide-rich diet. Our results also showed the physiological role of the kidneys in controlling excess circulating iodide. In addition, they revealed an active iodine cycle in the stomach. We also investigated the protective effects of daily KI administration during radioactive iodine exposure and found that the overall protection was better in rats (85%) than in mice (65%). We also included pregnant females and newborns, and we revealed the existence of specific mechanisms for the inhibition of the fetal thyroid by circulating iodine. Indeed, an iodine-rich diet or repeated daily administration of KI led to a strong inhibition of the iodide uptake capacity of the fetal thyroid. ConclusionsOur study contributes to a better understanding of iodine metabolism and its regulation in the thyroid and in non-thyroidal organs in adult, fetal and newborn animals. Extrapolated to humans, our results not only provide better understanding of iodide withdrawal as a clinical preparatory measure for patients with differentiated thyroid cancer, but also help to optimize countermeasures in the case of an exposure to radioactive iodine.

physiology↗

bioRxiv2020

Identification of oncolytic vaccinia restriction factors in canine high-grade mammary tumor cells using single-cell transcriptomics

Mammary carcinoma, including triple-negative breast carcinomas (TNBC) are tumor-types for which human and canine pathologies are closely related at the molecular level. Low-passage, primary carcinoma cells from TNBC versus non-TNBC were used to compare the efficacy of an oncolytic vaccinia virus (VV). We show that non-TNBC cells are 28 times more sensitive to VV than TNBC cells in which VV replication is impaired. Single-cell RNA-seq performed on two different TNBC cell samples infected or not with VV highlighted three distinct populations: naive cells, bystander cells, defined as cells exposed to the virus but not infected and infected cells. The transcriptome of these three populations showed striking variations in the modulation of pathways regulated by cytokines and growth factors. We hypothesized that the pool of genes expressed in the bystander populations was enriched in antiviral genes. Bio-informatic analysis suggested that the reduced activity of the virus was associated with a higher mesenchymal status of the cells. In addition, we demonstrate experimentally that high expression of one gene, DDIT4, is detrimental to VV production. Considering that DDIT4 is associated with a poor prognosis in various cancers including TNBC, out data highlight DDIT4 as a candidate resistance marker for oncolytic poxvirus therapy. This information could be used to design new generations of oncolytic poxviruses. Beyond the field of gene therapy, this study demonstrate that single-cell transcriptomics can be used to identify cellular factors influencing viral replication. Author summaryThe identification of cellular genes influencing viral replication/propagation have been studied using hypothesis-driven approaches and/or high-throughput RNA interference screens. In the present report, we propose a methodology based on single-cell transcriptomic. We have studied, in the context of oncolytic virothepary, the susc eptibility of primary, low-passage mammary carcinoma cells of canine origin from different grades to an oncolytic vaccinia virus (VV). We highlight a fault in replication of VV in cells originated from high-grade triple-negative breast carcinomas (TNBC). Single-cell RNA-seq performed on TNBC cell samples infected with VV suggested that the reduced activity of the virus was associated with a higher mesenchymal status of the cells. We also demonstrate that high expression of one gene, DDIT4, is detrimental to VV production. Considering that DDIT4 is associated with a poor prognosis in various cancers including TNBC, out data highlight DDIT4 as a candidate resistance marker for oncolytic poxvirus therapy. Beyond the field of cancer gene therapy, we demonstrate here that single-cell transcriptomics increases the arsenal of tools available to identify cellular factors influencing viral replication.

cancer biology↗