To date, there is no effective treatment available for patients with thyroid cancer (TC). In most cases, TC metastases fail to express the sodium/iodine (NIS) marker and do not respond to radioactive iodine, which is an effective non-surgical treatment for TC. Hence, there is a need to develop experimental animal models to elucidate the mechanism underlying tumorigenesis and metastasis formation, especially for formulating therapies for radioiodine-resistant patients.
newly Nature Communications The study revealed the human ability to summarize embryonic stem cells (hESCs) to illustrate the cellular hierarchy of the thyroid gland. Moreover, these cells have the ability to reproduce the neoplastic process using the CRISPR-based gene editing method.
Stady: Recapitulating histological patterns of thyroid cancer by engineering embryonic stem cells. Image credit: Meletius Veras/Shutterstock
background
Typically, follicular cell-derived ESCs are developed from follicular epithelial cells derived from the defective endoderm layer, which consist of differentiated and anatomically undifferentiated subtypes. The differentiated core TCs include common papillary (PTC) and follicular (FTC). In most cases, differentiated CSCs are slow-growing tumors with a favorable outcome. However, in some cases, differentiated PCs have shown a high risk of relapse and eventually lead to death.
Anaplastic TC (ATC) shows aggressive behavior by invading adjacent tissues and metastasizing to distant organs. This type of TC accounts for about 2% of all TC cases. ATC is generated either from the follicular thyroid epithelium gland by removal of biological features associated with iodine uptake or by the dedifferentiation process of pre-existing differentiated TC containing multiple mutations.
Although many studies have revealed many important aspects of TCs, the cell subpopulation in the lineage hierarchy related to the cell of origin for various TC histotypes, after the accumulation of somatic mutations, is poorly understood. Scientists have developed several models of carcinogenesis based on different follicular histotypes of ESCs that exhibit specific behavior. These models have been used to better understand the cell of origin. The major shortcomings of these models are their failure to quantify phenotypic and genetic variability between tumors in follicular cell-derived CSCs.
In mammals, tissue repair and homeostasis is associated with tissue-specific stem cells that can self-restore and differentiate. Studies of the hierarchical organization of adult tissues have played an important role in slowing the aging process, recovering from injury, and preventing cells from accumulating damage that can eventually cause cancer.
A progenitor cell-based model introduced the concept of tumorigenesis. This model hypothesized that stem cells are the source of tumor formation based on their longevity and ability to self-restore, which is essential for the accumulation of mutations. To better understand multiple pathology and behavior, it is necessary to develop a genetic mutation model that includes multiple mutations within the same ‘target cell’.
Although investigators have successfully identified a subpopulation of cancer stem cells (CSCs)/progenitor cells associated with TC initiation, the stage of change in the hierarchy is not clear.
About the study
Tumor events that occur in tissue-resident stem cells/progenitor cells during TC transformation were effectively reproduced in this study. Moreover, genetic mutations of tissue-resident progenitor cells have been linked to the developmental process of thyroid tumorigenesis. Therefore, the current research has raised understanding regarding the incidence of TC based on the presence of stem/progenitor cells in the thyroid gland.
The different histological phenotypes of TC were recapitulated based on the induction of specific genetic changes introduced by CRISPR-Cas9 into hESC-derived thyroid progenitor cells (TPCs) at day 22. CRISPR/Cas9 technology has been used previously to introduce oncogenic mutations in the breast, colon, or colon. or pancreatic organoids and induce neoplastic transformation.
Common genetic and epigenetic changes associated with TC have been discovered previously. These studies have identified two major signaling pathways, the MAPK and PI3K/AKT/mTOR signaling pathways, associated with TC, which induce uncontrolled cell division, longevity, and cell migration.
a Schematic model showing that the most common genetic alterations of TC (BRAFV600ENRASQ61RBRAFV600E/ TP53R248Q and NRASQ61R/ TP53R248Q) in the thyroid gland cell (TPC) recapitulate the different histotypes of TC (FTC, PTC, and ATC). From Note TP53R248Q Alone is not required to initiate TC. B A model of the ternary complex (TIMP1/MMP9/CD44) and KISS1R-driven pathways in engineered D22 TPCs. Complex formation of TIMP1 and pro-MMP9 activates MMP9 and subsequently leads to CD44 cleavage. CD44’s intracytoplasmic domain (CD44icd) translocates to the nucleus where it stimulates transcription of CD44v6. CD44v6 promotes TPC proliferation through the PI3K/AKT pathway. Kissingpeptins (KP) binding to KISS1R activates ERK and cooperates with MMP9 to promote transcription of EMT-related genes, including TWIST and SNAIL, leading to metastatic effusion.
Previous studies revealed this BRAF mutated in ~40% of PTCs, ~35% of FTCs, and ~55% of ATCs. found the current study BRAFV600E or NRASQ61R It recapitulates the PTC and FTC histological phenotypes, respectively, at the morphological, transcriptional, and phonotypic levels.
In line with previous studies, the current study revealed this TP53 The mutation alone cannot lead to TC tumorigenesis. However, in conjunction with BRAFV600E or NRASQ61Rcan produce undifferentiated CPCs rich in metastasis-associated gene signatures that show cell aggressive behavior in ATC.
Transcriptome analyzes of metastatic TC lesions of human patients combined with xenografts of TPCs containing BRAFV600E or NRASQ61R jointly with TP53R248Q The mutations indicated the appearance of the TIMP1/MMP9/CD44 complex. This complex plays an important role in TC promotion. It has also been observed that activation of KISS1/KISS1R signaling is essential for metastatic growth. Notably, a poor prognosis for TC was associated with a high level of KISS1/KISS1R expression. This may be a promising marker for treatment analysis effectiveness in advanced TC patients.
conclusions
The targets of KISS1R and TIMP1 may be considered in the future as adjunctive therapy to sensitize ATCs. Future studies could use the newly developed experimental model, based on transgenic hESC-derived cells, to investigate genes and pathways that promote treatment resistance. In addition, this model can be used to study the mechanisms of tumorigenesis in different organs.
