Though heterogeneity of cancers is recognized and has been much discussed in recent years, the concept often remains overlooked in different routine examinations. Indeed, in clinical or biological articles, reviews, and textbooks, cancers and cancer cells are generally presented as evolving distinct entities rather than as an independent heterogeneous cooperative cell population with its self-oriented biology. There are, therefore, conceptual gaps which can mislead the interpretations/diagnostic and therapeutic approaches. In this short review, we wish to summarize and discuss various aspects of this dynamic evolving heterogeneity and its biological, pathological, clinical, diagnostic, and therapeutic implications, using thyroid carcinoma as an illustrative example.

The human thyroid gland acquires a differentiation program as early as weeks 3–4 of embryonic development. The onset of functional differentiation, which manifests by the appearance of colloid in thyroid follicles, takes place during gestation weeks 10–11. By 12–13 weeks functional differentiation is accomplished and the thyroid is capable of producing thyroid hormones although at a low level. During maturation, thyroid hormones yield increases and physiological mechanisms of thyroid hormone synthesis regulation are established. In the present work we traced the process of thyroid functional differentiation and maturation in the course of human development by performing transcriptomic analysis of human thyroids covering the period of gestation weeks 7–11 and comparing it to adult human thyroid. We obtained specific transcriptomic signatures of embryonic and adult human thyroids by comparing them to non-thyroid tissues from human embryos and adults. We defined a non-TSH (thyroid stimulating hormone) dependent transition from differentiation to maturation of thyroid. The study also sought to shed light on possible factors that could replace TSH, which is absent in this window of gestational age, to trigger transition to the emergence of thyroid function. We propose a list of possible genes that may also be involved in abnormalities in thyroid differentiation and/or maturation, hence leading to congenital hypothyroidism. To our knowledge, this study represent the first transcriptomic analysis of human embryonic thyroid and its comparison to adult thyroid.

Tumors originating from thyroid follicular cells are the most common endocrine tumors, with rising incidence. Despite a generally good prognosis, up to 20% of patients experience recurrence and persistence, highlighting the need to identify the underlying molecular mechanisms. Dicer1 has been found to be altered in papillary thyroid cancer (PTC). Studies suggest that Dicer1 functions as a haploinsufficient tumor suppressor gene: partial loss promotes tumorigenesis, while complete loss prevents it. To investigate the effects of partial or total Dicer1 loss in PTC in vitro, we generated stable Dicer1 (+/−) cell lines from TPC1 using CRISPR-Cas9, though no Dicer1 (−/−) lines could be produced. Therefore, siRNA against Dicer1 was transfected into Dicer1 (+/−) cell lines to further decrease its expression. Transcriptomic analysis revealed changes in proliferation and cell locomotion. BrdU staining indicated a slow-down of the cell cycle, with fewer cells in S phase and more in G0-G1-phase. Additionally, transwell assays showed decreased invasion and migration after Dicer1 knockdown by siRNA. Moreover, Dicer1 overexpression led to decreased proliferation, invasion, and increased apoptosis. Our findings deepen the understanding of Dicer1’s role in thyroid cancer, demonstrating that both complete elimination and overexpression of Dicer1 inhibit thyroid oncogenesis, highlighting Dicer1 as a promising target for novel therapeutic strategies.

Background: The diagnosis of malignant thyroid nodules is mainly based on the fine-needle aspiration biopsy (FNAB). To improve the detection of malignant nodules, different molecular tests have been developed. We present a new molecular signature based on altered miRNA expressions and specific mutations. Methods: This is a prospective non-interventional study, including all Bethesda categories, carried out on an FNAB sampled in suspicious nodule(s) during thyroidectomy. miRNA quantification and mutations detection were performed. The reference diagnosis was the pathological assessment of the surgical specimen. Different classification algorithms were trained with molecular data to correctly classify the samples. Results: A total of 294 samples were recorded and randomly divided in two equal groups. The random forest algorithm showed the highest accuracy and used mostly miRNAs to classify the nodules. The sensitivity and the specificity of our signature were, respectively, 76% and 96%, and the positive and negative predictive values were both 90% (disease prevalence of 30%). Conclusions: We have identified a molecular classifier that combines miRNA expressions with mutations detection. This signature could potentially help clinicians, as complementary to the Bethesda classification, to discriminate indeterminate FNABs.

Beyond well-known genetic drivers, microRNA dysregulation has emerged as a key contributor to thyroid tumorigenesis. Central to this process is Dicer1, a ribonuclease essential for microRNA maturation, whose expression is often reduced in papillary thyroid carcinoma (PTC). Evidence from previous studies suggest Dicer1 functions as a context-dependent haplo-insufficient tumor suppressor gene: partial loss may promote tumor development, whereas complete loss may disrupt essential cellular functions, causing cell death and tumor suppression. However, the effects of partial or complete Dicer1 loss in thyroid cancer remain unclear. To explore this, we genetically inactivated one (heterozygous) or both (homozygous) Dicer1 alleles specifically in thyroid follicular cells of a RET/PTC3 transgenic mouse model using an inducible Cre-Lox system. Our findings deepen the current understanding of the RET/PTC3-driven PTC model by revealing an increased number of vimentin-positive cells and disruption in redox homeostasis. Additionally, whereas heterozygous Dicer1 loss did not alter tumor progression in RET/PTC3 mice, total loss reduced tumor growth and led to accumulated DNA damage and cell death. These findings highlight the crucial role of Dicer1 dosage in thyroid cancer progression and underscore its potential as a therapeutic target for aggressive PTC and other malignancies characterized by aberrant Dicer1 expression.

Thyroid cancer is the most prevalent endocrine malignancy, and papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Although the prognosis is generally favorable, a better understanding of the molecular mechanisms involved in this pathology could lead to new treatment opportunities. Dysregulation of miRNA expression has been correlated with tumor development, and miR-1179 has been previously identified as one of the most downregulated miRNAs in PTC. This study aimed to explore the role of miR-1179 in thyroid tumorigenesis. miR-1179 was overexpressed in the TPC-1, B-CPAP, and HTori-3 thyroid cell lines to characterize its function and identify mRNA targets. The relevance of our data for human PTC was then addressed by analyzing TCGA and independent PTC. We showed that miR-1179 triggered apoptosis and inhibited cell migration. We identified ELF3 as a direct target of miR-1179 and other effectors, including NOTCH3 and CX3CL1. Finally, we revealed the existence of an inverse correlation between decreased expression of miR-1179 and increased expression of ELF3, NOTCH3, and CX3CL1 mRNA in human PTC. Our findings suggest that miR-1179 is a tumor suppressor gene and that its loss may contribute to thyroid tumor progression by promoting the expression of ELF3, NOTCH3, and CX3CL1.