Aug 2026· Nature Reviews Endocrinology· 0 citations· 101 references
Medicine
TL;DR
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.
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
Collectively, the advances are an indication of a transition to the personalized, mechanism-driven treatment strategies that would prolong the survivability of patients with advanced thyroid cancer, conquer resistance, and reduce systemic toxicity.
Tanmoy Sarkar, Ruhi Arisha, S. Sengupta et al.· Clinical and Translational O...· 0 citations
Cutaneous squamous cell carcinoma (cSCC) is the second most common form of cancer worldwide. While most cSCCs are not life-threatening, 2-5% of patients develop metastases. To better understand what causes some cSCCs to progress to metastatic disease, we assembled a nationwide cohort of 19,120 patients with clinico-pathologically annotated tumors linked to metastatic outcome. RNA-sequencing was performed on 378 tumors, and whole-exome sequencing on 147, with balanced numbers of tumors that progressed to metastatic disease (cases) and did not (controls). UV radiation was the dominant mutational signature with additional contributions from aging, APOBEC activity, and, in immunosuppressed patients, azathioprine exposure. We identified 38 genes under selection across a core set of signaling pathways. Gene expression clusters were primarily associated with the differentiation state of tumor cells and secondarily with the composition of the tumor microenvironment. Several mutational and transcriptional programs were associated with metastasis, including a dedifferentiated gene expression signature, activating mutations in the RAS signaling pathway, loss-of-function alterations in the SWI/SNF chromatin remodeling complex, and specific arm-level copy number alterations. A 23-gene expression signature was built to predict metastasis from primary cSCC tissue. The signature was validated in two independent cohorts (N=102 and 52), where it predicted metastasis independently of staging systems. Together, these findings provide the most detailed molecular portrait of cSCC to date and establish an assay for risk stratification suitable for clinical implementation.
B. Rentroia-Pacheco, Harsh Sharma, L. Pozza et al.· medRxiv· 0 citations
This study comprehensively maps the coevolution of malignant thyrocyte plasticity and the immunosuppressive metastatic niche in thyroid cancer and provides a robust molecular rationale for developing next-generation immunotherapeutic strategies tailored to thyroid cancer.
Shu-hang Xu, Yaorong Su, Senmin Zhang et al.· Oncoimmunology· 0 citations
Thyroid cancer comprises a biologically diverse group of tumors initiated by a limited number of recurrent driver alterations, with additional molecular events promoting dedifferentiation, therapeutic resistance, and aggressive clinical behavior. Advances in tumor sequencing have clarified the molecular architecture of papillary, follicular, oncocytic, poorly differentiated, anaplastic, and medullary thyroid carcinomas, and have already changed management in selected settings. Molecular testing improves diagnostic refinement and risk assessment in cytologically indeterminate thyroid nodules, while alterations involving BRAF, RET, and NTRK can guide targeted therapy in advanced disease. Beyond DNA, transcriptomic, proteomic, epigenetic, metabolomic, immune, spatial, and liquid-biopsy approaches offer functional insight into differentiation state, treatment sensitivity, and resistance, although most remain investigational. Their clinical value depends not only on biological plausibility, but on reproducibility, incremental value beyond established clinicopathological variables, and the ability to alter patient management. Computational tools may further support integration of molecular and clinical data, but their usefulness likewise depends on calibration, external validation, interpretability, and demonstration of decision impact. This review synthesizes the genomic and multi-omics determinants of thyroid cancer management across diagnosis, risk stratification, treatment selection, resistance monitoring, and follow-up, and discusses the practical barriers that continue to limit routine implementation, including assay standardization, cost, access, and real-world feasibility. Progress in precision thyroid oncology will depend on robust validation of emerging biomarkers and clear evidence that they improve patient outcomes.
Dhoha Dhieb, Kholoud Bastaki· International Journal of Mol...· 0 citations
This comprehensive review highlights BMBC resistance mechanisms, drawing from preclinical models, clinical studies, and genomic analyses, and highlights the potential for personalized, multi-targeted approaches to improve patient outcomes in BMBC.
Paromita Sarker, Shreyas S Rao· Biochimica et biophysica act...· 0 citations
