Together, the findings reveal mutation-dependent epithelial and TME dynamics associated with thyroid cancer dedifferentiation and highlight the potential importance of molecular-tailored approaches in the management of advanced thyroid cancer.
Abstract
Progression from differentiated thyroid cancer to anaplastic thyroid cancer (ATC) involves profound epithelial plasticity and remodeling of the tumor microenvironment (TME), but how BRAFV600E and RAS driver mutations shape these processes remains unclear. Here, we integrated single-nucleus RNA-seq, spatial transcriptomics, and bulk RNA-seq across BRAFV600E- and RAS-driven thyroid tumors to delineate mutation-specific progression trajectories. BRAFV600E-driven tumors exhibited a gradual dedifferentiation trajectory with immune pathway activation, whereas RAS-driven tumors displayed abrupt transitions characterized by aneuploidy, epithelial–mesenchymal transition, hypoxia, and extracellular matrix remodeling. Cancer-associated fibroblasts (CAFs) emerged as key regulators, with mutation-specific ligand–receptor interactions: integrin-based signaling predominated in BRAFV600E-mutant ATCs, while PLAU–PLAUR, TNFSF10–TNFRSF10B, and AREG–EGFR were additionally enriched in RAS-driven ATCs. These CAF–epithelial circuits were spatially validated and associated with poor prognosis. Together, our findings reveal mutation-dependent epithelial and TME dynamics associated with thyroid cancer dedifferentiation and highlight the potential importance of molecular-tailored approaches in the management of advanced thyroid cancer.
Thyroid cancer ranges from indolent differentiated tumors to metastatic, radioiodine-refractory and anaplastic disease. Conventional histology and molecular classification define major risk groups but do not resolve the cell states and spatial heterogeneity that accompany progression. This review integrates recent single-cell RNA sequencing, spatial transcriptomics and validation studies across localized papillary thyroid carcinoma (PTC), metastatic or radioiodine-refractory differentiated thyroid cancer (DTC), poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC). Current evidence indicates that progression is accompanied by changes in malignant epithelial states, stromal regions and immune patterns. Malignant epithelial cells shift from follicular-like programs toward partial EMT-like, dedifferentiation-like and anaplastic states; stromal changes include invasive borders, stiff peritumoral matrix and CAF/ECM-rich poorly differentiated regions; and immune patterns differ between progressive PTC, indolent lymphoid-organized tumors and myeloid-rich ATC. Functionally supported examples, including POSTN-IL-4 signaling, CCL20/CXCL5 macrophage-tumor reciprocal signals and SIGLEC15-associated checkpoint signaling, show how these technologies can generate therapeutic hypotheses. Yet most datasets are cross-sectional, and many ligand-receptor interactions remain computational candidates. We use the available evidence to relate epithelial plasticity, genomic context, stromal regions, immune remodeling and candidate cell-cell interactions across disease states, while separating observed associations from established stepwise tumor evolution. This synthesis highlights mechanisms and therapeutic hypotheses that require functional and clinical validation.
Xin Wang, Deshuang Tao, Jinming Xu et al.· Frontiers in Immunology· 0 citations
Anaplastic thyroid carcinoma (ATC) is a rare, highly aggressive follicular cell-derived malignancy characterized by rapid progression, profound dedifferentiation, and marked resistance to conventional therapy. Despite frequent involvement of major oncogenic pathways, ATC does not exhibit a universal driver mutation, suggesting that its pathogenesis reflects convergence upon shared biological hallmarks rather than dependence on a single molecular event. This review describes the principal mechanistic programs that define the ATC phenotype: disruption of cell-cycle and apoptotic control through alterations in TP53, CDKN2A/B, and aberrant MAPK activation; metabolic adaptations involving glycolysis, glutaminolysis, and mitochondrial one-carbon metabolism; reprogramming of canonical stress response pathways including ER stress and hypoxia signaling; and dynamic remodeling of the tumor microenvironment through cytokine-driven paracrine networks and immune modulation. Collectively, these processes cooperate to generate a highly proliferative, stress-tolerant, immune-inflamed yet immunosuppressed tumor state. A mechanistic understanding of these convergent pathways is essential for rational therapeutic development and for overcoming the profound clinical resistance that defines ATC.
Anthony Centone, N. Desouza, Nan Yang et al.· International Journal of Mol...· 0 citations
Progress in the understanding of ATC biology is highlighted, with a focus on driver genetic alterations, metabolic plasticity and microenvironmental interactions that underpin its exceptional aggressiveness, to provide a rationale for the design of multimodal therapeutic strategies urgently needed to improve outcomes for patients with ATC.
Background APOBEC cytidine deaminases generate characteristic TCW-context mutations that diversify cancer genomes, yet their functional impact on colorectal cancer (CRC) progression and the tumor microenvironment (TME) remains poorly defined. Methods We integrated whole-exome sequencing, bulk and single-cell transcriptomics from multi-cohort datasets, supported by functional assays and in vivo xenograft models, to delineate the biological and clinical consequences of APOBEC activation in CRC. A machine-learning framework was used to derive an APOBEC activation–associated transcriptional signature (AAS). Results Across multi-cohort datasets, AAS defined a colorectal cancer subtype with enriched TCW mutagenesis and significantly worse survival. High AAS tumors were associated with coordinated remodeling of the TME, including increased fibroblast and endothelial signatures and reduced cytotoxic immune infiltration. Single-cell analyses suggested that high AAS tumors were enriched for endothelial states with arterial and pro-angiogenic features. Conditioned-medium experiments further supported a potential tumor cell secretome-mediated link between APOBEC3B activation and endothelial transcriptional remodeling. Integrative analyses identified PCDH9 as a candidate APOBEC-associated target linked to Hippo, Wnt/β-catenin, and TGF-β signaling alterations, while mutation-specific causality remains to be experimentally validated. Conclusions This multi-omics study identifies APOBEC activity as a central orchestrator of CRC evolution, associated with stromal-vascular remodeling and intracellular oncogenic activation through PCDH9-associated signaling alterations. The AAS provides a robust prognostic biomarker and highlights APOBEC-high tumors as candidates for anti-angiogenic therapy and for interventions targeting APOBEC-induced signaling vulnerabilities.
Junting Chen, Jiaming Cao, Baosen Zhou et al.· Frontiers in Immunology· 0 citations
Head and neck squamous cell carcinoma (HNSCC) remains clinically challenging, with limited molecularly targeted options and a strong dependence on the tumor microenvironment. Cancer-associated fibroblasts (CAFs) are major stromal regulators that shape tumor progression, extracellular matrix remodeling, invasion, and therapeutic response. However, how CAF heterogeneity and plasticity translate into distinct tumor-promoting functions and targetable vulnerabilities remains insufficiently defined. Here, we integrated patient-matched primary CAFs and normal fibroblasts with 3D functional assays, tumor–stroma co-culture models, quantitative extracellular matrix analysis, whole-proteome profiling, and pharmacological perturbation. Primary fibroblast populations displayed marked interpatient heterogeneity and context-dependent plasticity in invasion, contractility, and responsiveness to tumor-derived signals, whereas enhanced fibronectin-rich matrix deposition and disorganization emerged as a conserved CAF-associated feature. Both normal fibroblasts and CAFs promoted HNSCC cell invasion in a population-dependent manner, whereas CAFs consistently induced less compact and more dispersed tumor nest architectures. Integrative functional analyses identified distinct CAF phenotypes characterized by either invasive and matrix-remodeling activity or high responsiveness to tumor-derived cues. Proteomic profiling revealed recurrent enrichment of adhesion, cytoskeletal, and extracellular matrix programs and guided the selection of pharmacological inhibitors aimed at modulating specific CAF-mediated pro-tumoral functions. Pharmacological targeting selectively altered these functions: CHI3L1 inhibition disrupted fibronectin matrix deposition, broad phosphodiesterase inhibition increased matrix alignment, and FZD7 inhibition consistently blocked tumor-induced CAF invasion across all tested populations. These findings define functionally distinct and pharmacologically targetable CAF programs in HNSCC and support stromal-directed interventions as a rational component of future combination treatment strategies.
Llara Prieto-Fernández, A. Martínez-Carrillo, Lucas de Villalaín et al.· bioRxiv· 0 citations
Tumor progression and metastasis in bladder cancer are driven by epithelial cell heterogeneity and dynamic interactions with the tumor microenvironment. To elucidate epithelial subpopulations associated with cancer progression, we performed single-cell transcriptomic profiling of bladder cancer tissues and identified a distinct epithelial subset, termed Meta-program 6 (MP6), that was significantly enriched in samples exhibiting lymphovascular invasion or lymph node metastasis. The MP6 gene signature correlated strongly with advanced tumor stage, lymph node involvement, and lymphovascular infiltration. CNV analysis revealed extensive chromosomal alterations, particularly chromosome 19 deletion, indicating genomic instability. Cell–cell communication analysis demonstrated active crosstalk between MP6 tumor cells and cancer-associated fibroblasts, including WNT and BMP signaling pathways, indicating that stromal crosstalk may contribute to the establishment of a pro-tumorigenic microenvironment. Transcription factor network inference further identified elevated activity of regulators such as TFCP2 and ELF1, implicating them in the acquisition of aggressive phenotypes. Immunohistochemical validation supported the clinical relevance of selected MP6-associated targets. Collectively, these findings define a clonally evolved epithelial subtype associated with lymphatic invasion and provide mechanistic insights into tumor cell plasticity and stromal–epithelial interactions underlying bladder cancer progression.
Yongxiang Luo, Xiaoping Liu, Sihua Zhu et al.· Frontiers in Cell and Develo...· 0 citations
