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Dedifferentiation patterns in DTC: is PDTC an intermediate state between DTC and ATC?

ABSTRACT: PURPOSE:The majority of poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are thought to dedifferentiated from differentiated thyroid cancer (DTC). PDTC is regarded as an intermediate form, through which DTC dedifferentiates into ATC. Although accumulation of gene mutations has been observed in PDTC and ATC, evidence of a direct link between DTC, PDTC, and ATC is still lacking. This work aims to illustrate if PDTC is the intermediate state between DTC and ATC. PATIENTS AND METHODS:Whole-exome sequencing was performed in a single patient presenting with primary papillary thyroid cancer (PTC) with simultaneous PTC, PDTC, and ATC in metastatic lymph nodes. RESULTS:167 nonsynonymous mutations were identified, and 24 of them were exclusive to metastatic loci. Comparison of mutational spectra revealed following results: 1) PDTC and ATC were associated with PTC-LN2 but not PTC-LN1; 2) the majority (5/6) of non-ubiquitous mutations in ATC were also present in PDTC; and 3) despite one mutation observed simultaneously in PTC-LN2, PDTC and ATC, no other associations were found between the ATC and PTC samples (primary or metastatic). Additionally, we identified five mutations (four mutations present in both PDTC and ATC, and one exclusive to ATC), including TP53 p.N107_S108delinsX, possibly related with DTC dedifferentiation. CONCLUSIONS:We observed an apparent potential, stepwise dedifferentiation process linking DTC, PDTC, and ATC, with PDTC serving as an intermediate state between DTC and ATC in one certain patient. One key mutation, combined with several low-frequency mutations, appears to underlie this dedifferentiation pathway.

SUBMITTER: Wen D

PROVIDER: S-EPMC6944019 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Dedifferentiation patterns in DTC: is PDTC an intermediate state between DTC and ATC?

Wen Duo D Hu Jia-Qian JQ Wei Wen-Jun WJ Ma Ben B Lu Zhong-Wu ZW Wang Yu-Long YL Wang Yu Y Ji Qing-Hai QH

International journal of clinical and experimental pathology 20190101 1

<h4>Purpose</h4>The majority of poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are thought to dedifferentiated from differentiated thyroid cancer (DTC). PDTC is regarded as an intermediate form, through which DTC dedifferentiates into ATC. Although accumulation of gene mutations has been observed in PDTC and ATC, evidence of a direct link between DTC, PDTC, and ATC is still lacking. This work aims to illustrate if PDTC is the intermediate state between DTC and AT ...[more]

PMID: 31933742

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Project description:BackgroundCellular dedifferentiation is a regenerative prerequisite that warrants cell cycle reentry and appropriate mitotic division during de novo formation of cardiomyocytes. In the light of our previous finding that expression of injury-responsive element, Wilms Tumor factor 1 (WT1), in pericardial adipose stromal cells (ADSC) conferred a compelling reparative activity with concomitant IL-6 upregulation, we then aim to unravel the mechanistic network that governs the process of regenerative dedifferentiation after ADSC-based therapy.Methods and resultsWT1-expressing ADSC (eGFP:WT1) were irreversibly labeled in transgenic mice (WT1-iCre/Gt(ROSA)26Sor-eGFP) primed with myocardial infarction. EGFP:WT1 cells were enzymatically isolated from the pericardial adipose tissue and cytometrically purified (ADSCgfp+). Bulk RNA-seq revealed upregulation of cardiac-related genes and trophic factors in ADSCgfp+ subset, of which IL-6 was most abundant as compared to non-WT1 ADSC (ADSCgfp-). Injection of ADSCgfp+ subset into the infarcted hearts yielded striking structural repair and functional improvement in comparison to ADSCgfp- subset. Notably, ADSCgfp+ injection triggered significant quantity of dedifferentiated cardiomyocytes recognized as round-sharp, marginalization of sarcomeric proteins, expression of molecular signature of non-myogenic genes (Vimentin, RunX1), and proliferative markers (Ki-67, Aurora B and pH3). In the cultured neonatal cardiomyocytes, spontaneous dedifferentiation was accelerated by adding tissue extracts from the ADSC-treated hearts, which was neutralized by IL-6 antibody. Genetical lack of IL-6 in ADSC dampened cardiac dedifferentiation and reparative activity.ConclusionsTaken collectively, our results revealed a previous unappreciated effect of IL-6 on cardiac dedifferentiation and regeneration. The finding, therefore, fulfills the promise of stem cell therapy and may represent an innovative strategy in the treatment of ischemic heart disease.

Dataset Information

Dedifferentiation patterns in DTC: is PDTC an intermediate state between DTC and ATC?

Publications

Dedifferentiation patterns in DTC: is PDTC an intermediate state between DTC and ATC?

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