A zebrafish xenotransplant model of anaplastic thyroid cancer to study tumor microenvironment and innate immune cell interactions in vivo.

Anaplastic thyroid cancer (ATC) is of the most aggressive thyroid cancer. While ATC is rare, it accounts for a disproportionately high number of thyroid cancer-related deaths. Here, we developed an ATC xenotransplant model in zebrafish larvae, where we can study tumorigenesis and therapeutic response in vivo.

Anaplastic thyroid cancer cells upregulate mitochondrial one-carbon metabolism to meet purine demand, eliciting a critical targetable vulnerability.

Anaplastic thyroid cancer (ATC) is one of the most aggressive and lethal tumor types, characterized by loss of differentiation, epithelial-to-mesenchymal transition, extremely high proliferation rate, and generalized resistance to therapy. To identify novel relevant, targetable molecular alterations, we analyzed gene expression profiles from a genetically engineered ATC mouse model and from human patient datasets, and found consistent upregulation of genes encoding enzymes involved in the one-carbon metabolic pathway, which uses serine and folates to generate both nucleotides and glycine. Genetic and pharmacological inhibition of SHMT2, a key enzyme of the mitochondrial arm of the one-carbon pathway, rendered ATC cells glycine auxotroph and led to significant inhibition of cell proliferation and colony forming ability, which was primarily caused by depletion of the purine pool.

A zebrafish xenotransplant model of anaplastic thyroid cancer to study the tumor microenvironment and innate immune cell interactions .

Anaplastic thyroid cancer (ATC) is a rare malignant subtype of thyroid cancer. While ATC is rare it accounts for a disproportionately high number of thyroid cancer-related deaths. Here we developed an ATC xenotransplant model in zebrafish larvae, where we can study tumorigenesis and therapeutic response in vivo.

Anaplastic Thyroid Cancer Cells Upregulate Mitochondrial One-Carbon Metabolism To Meet Purine Demand, Eliciting A Critical Targetable Vulnerability.

Anaplastic thyroid cancer (ATC) is one of the most aggressive and lethal tumor types, characterized by loss of differentiation, epithelial-to-mesenchymal transition, extremely high proliferation rate, and generalized resistance to therapy. To identify novel relevant, targetable molecular alterations, we analyzed gene expression profiles from a genetically engineered ATC mouse model and from human patient datasets, and found consistent upregulation of genes encoding enzymes involved in the one-carbon metabolic pathway, which uses serine and folates to generate both nucleotides and glycine. Genetic and pharmacological inhibition of , a key enzyme of the mitochondrial arm of the one-carbon pathway, rendered ATC cells glycine auxotroph and led to significant inhibition of cell proliferation and colony forming ability, which was primarily caused by depletion of the purine pool.

The Year in Basic Thyroid Cancer Research.

Every year, the American Thyroid Association (ATA) Annual Meeting opening session features presentations covering the most recent advances in the three major areas of thyroidology: basic, clinical, and surgical. As the ATA did not have an annual meeting in 2020, because of the COVID19 pandemic, the 2021 meeting opened with a special "Two Years in Thyroidology" session. A PubMed electronic search was conducted to identify original basic science research studies on thyroid cancer published between October 2019 and September 2021.

2021 American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer.

Anaplastic thyroid cancer (ATC) is a rare but highly lethal form of thyroid cancer. Since the guidelines for the management of ATC by the American Thyroid Association were first published in 2012, significant clinical and scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, and researchers on published evidence relating to the diagnosis and management of ATC.

Real-time, high-resolution imaging of tumor cells in genetically engineered and orthotopic models of thyroid cancer.

Genetically engineered and orthotopic xenograft mouse models have been instrumental for increasing our understanding of thyroid cancer progression and for the development of novel therapeutic approaches in a setting that is more physiologically relevant than the classical subcutaneous flank implants. However, the anatomical location of the thyroid gland precludes a non-invasive analysis at the cellular level of the interactions between tumor cells and the surrounding microenvironment and does not allow a real-time evaluation of the response of tumor cells to drug treatments. As a consequence, such studies have generally only relied on endpoint approaches, limiting the amount and depth of the information that could be gathered.

Metabolic Role of PTEN in Insulin Signaling and Resistance.

Phosphatase and tensin homolog (PTEN) is most prominently known for its function in tumorigenesis. However, a metabolic role of PTEN is emerging as a result of its altered expression in type 2 diabetes (T2D), which results in impaired insulin signaling and promotion of insulin resistance during the pathogenesis of T2D. PTEN functions in regulating insulin signaling across different organs have been identified.

Synergistic repression of thyroid hyperplasia by cyclin C and Pten.

The cyclin C-Cdk8 kinase has been identified as both a tumor suppressor and an oncogene depending on the cell type. The genomic locus encoding cyclin C () is often deleted in aggressive anaplastic thyroid tumors. To test for a potential tumor suppressor role for cyclin C, alone, or in combination with a previously described thyroid tumor suppressor , was deleted late in thyroid development.

PI3K/mTOR inhibition potentiates and extends palbociclib activity in anaplastic thyroid cancer.

Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer. Despite its low incidence, it accounts for a disproportionate number of thyroid cancer-related deaths, because of its resistance to current therapeutic approaches. Novel actionable targets are urgently needed to prolong patient survival and increase their quality of life.

PI3K blockage synergizes with PLK1 inhibition preventing endoreduplication and enhancing apoptosis in anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is among the most lethal malignancies. The mitotic kinase PLK1 is overexpressed in the majority of ATCs and PLK1 inhibitors have shown preclinical efficacy. However, they also cause mitotic slippage and endoreduplication, leading to the generation of tetraploid, genetically unstable cell populations.

SGK1 Is a Critical Component of an AKT-Independent Pathway Essential for PI3K-Mediated Tumor Development and Maintenance.

Activation of the PI3K-AKT signaling cascade is a common critical event during malignant transformation. In this study, we used thyroid gland epithelial cells and a series of genetically engineered mouse strains as model systems to demonstrate that, although necessary, AKT activation is not sufficient for PI3K-driven transformation. Instead, transformation requires the activity of the PDK1-regulated AGC family of protein kinases.

SGK1: The Dark Side of PI3K Signaling.

Activation of the PI3K pathway is central to a variety of physiological and pathological processes. In these contexts, AKT is classically considered the de facto mediator of PI3K-dependent signaling. However, in recent years, accumulating data point to the existence of additional effectors of PI3K activity, parallel to and independent of AKT, that play critical and unique roles in mediating different developmental, homeostatic, and pathological processes.

Obatoclax kills anaplastic thyroid cancer cells by inducing lysosome neutralization and necrosis.

Poorly differentiated and anaplastic thyroid carcinomas are very aggressive, almost invariably lethal neoplasms for which no effective treatment exists. These tumors are intrinsically resistant to cell death, even when their driver oncogenic signaling pathways are inhibited.We have undertaken a detailed analysis, in mouse and human thyroid cancer cells, of the mechanism through which Obatoclax, a pan-inhibitor of the anti-apoptotic proteins of the BCL2 family, effectively reduces tumor growth in vitro and in vivo.

MCM5 as a target of BET inhibitors in thyroid cancer cells.

Anaplastic thyroid carcinoma (ATC) is an extremely aggressive thyroid cancer subtype, refractory to the current medical treatment. Among various epigenetic anticancer drugs, bromodomain and extra-terminal inhibitors (BETis) are considered to be an appealing novel class of compounds. BETi target the bromodomain and extra-terminal of BET proteins that act as regulators of gene transcription, interacting with histone acetyl groups.

Modeling anaplastic thyroid carcinoma in the mouse.

Anaplastic thyroid carcinoma is the least common form of thyroid cancer; however, it accounts for the majority of deaths associated with this family of malignancies. A number of genetically engineered immunocompetent mouse models recapitulating the genetic and histological features of anaplastic thyroid cancer have been very recently generated and represent an invaluable tool to dissect the mechanisms involved in the progression from indolent, well-differentiated tumors to aggressive, undifferentiated carcinomas and to identify novel therapeutic targets. In this review, we focus on the relevant characteristics associated with these models and on what we have learned in terms of anaplastic thyroid cancer biology, genetics, and response to targeted therapy.

Obatoclax overcomes resistance to cell death in aggressive thyroid carcinomas by countering Bcl2a1 and Mcl1 overexpression.

Poorly differentiated tumors of the thyroid gland (PDTC) are generally characterized by a poor prognosis due to their resistance to available therapeutic approaches. The relative rarity of these tumors is a major obstacle to our understanding of the molecular mechanisms leading to tumor aggressiveness and drug resistance, and consequently to the development of novel therapies. By simultaneously activating Kras and deleting p53 (Trp53) in thyroid follicular cells, we have generated a novel mouse model that develops papillary thyroid cancer invariably progressing to PDTC.

Inhibition of AMPK and Krebs cycle gene expression drives metabolic remodeling of Pten-deficient preneoplastic thyroid cells.

Rapidly proliferating and neoplastically transformed cells generate the energy required to support rapid cell division by increasing glycolysis and decreasing flux through the oxidative phosphorylation (OXPHOS) pathway, usually without alterations in mitochondrial function. In contrast, little is known of the metabolic alterations, if any, which occur in cells harboring mutations that prime their neoplastic transformation. To address this question, we used a Pten-deficient mouse model to examine thyroid cells where a mild hyperplasia progresses slowly to follicular thyroid carcinoma.

Molecular differences between human thyroid follicular adenoma and carcinoma revealed by analysis of a murine model of thyroid cancer.

Mouse models can provide useful information to understand molecular mechanisms of human tumorigenesis. In this study, the conditional thyroid mutagenesis of Pten and Ras genes in the mouse, which induces very aggressive follicular carcinomas (FTCs), has been used to identify genes differentially expressed among human normal thyroid tissue (NT), follicular adenoma (FA), and FTC. Global gene expression of mouse FTC was compared with that of mouse normal thyroids: 911 genes were found deregulated ± 2-fold in FTC samples.

Three-dimensional nuclear telomere architecture changes during endometrial carcinoma development.

Endometrioid or type-I endometrial carcinoma (EC) develops from hyperproliferative glandular pathologies. Inactivation of the tumor suppressor gene PTEN is frequently associated with type-I EC. Using a previously characterized Pten heterozygous (Pten+/-) mouse model, this study investigates the three-dimensional (3D) telomere profiles during progression from hyperplastic lesions to EC to test the hypothesis that altered 3D telomere profiles can be detected prior to Pten loss in early hyperproliferative lesions.

The PLK1 inhibitor GSK461364A is effective in poorly differentiated and anaplastic thyroid carcinoma cells, independent of the nature of their driver mutations.

Background: Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are the most aggressive forms of thyroid cancer. Despite their low incidence, they account for a disproportionate number of thyroid cancer-related deaths because of their resistance to most therapeutic approaches. We have generated mouse models that develop ATC ([Pten, p53](thyr-/-) mice) and follicular thyroid cancer with areas of poor differentiation (Pten(thyr-/-),Kras(G12D) mice).

New routes to old places: PIK3R1 and PIK3R2 join PIK3CA and PTEN as endometrial cancer genes.

Cheung and colleagues identify PIK3R1 and PIK3R2, the genes encoding the α and β isoforms of the phosphatidylinositol 3-kinase (PI3K) p85 regulatory subunit, as additional mutation targets in endometrial cancer, and describe a novel mechanism leading to PTEN loss.

Thyrocyte-specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors.

Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer, and often derives from pre-existing well-differentiated tumors. Despite a relatively low prevalence, it accounts for a disproportionate number of thyroid cancer-related deaths, due to its resistance to any therapeutic approach. Here we describe the first mouse model of ATC, obtained by combining in the mouse thyroid follicular cells two molecular hallmarks of human ATC: activation of PI3K (via Pten deletion) and inactivation of p53.

Embryonic epithelial Pten deletion through Nkx2.1-cre leads to thyroid tumorigenesis in a strain-dependent manner.

Even though the role of the tyrosine phosphatase Pten as a tumor suppressor gene has been well established in thyroid cancer, its role during thyroid development is still elusive. We therefore targeted Pten deletion in the thyroid epithelium by crossing Pten(flox/flox) with a newly developed Nkx2.1-cre driver line in the BALB/c and C57BL/6 genetic backgrounds.