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Although ATC frequently involves major oncogenic pathways, it lacks a universal driver mutation, indicating pathogenesis through converging shared biological hallmarks. The review details mechanistic programs that shape ATC phenotype, including dysregulated TP53/CDKN2A/B cell-cycle and apoptosis, MAPK-driven signaling, metabolic rewiring, stress-response reprogramming, and tumor microenvironment remodeling via cytokine networks and immune modulation. These processes reinforce a proliferative, stress-tolerant, immune-inflamed yet immunosuppressed state. Mechanistic insight supports rational therapeutic development and aims to overcome clinical resistance.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/convergent-mechanistic-pathways-driving-the-anaplastic-phenotype-in-thyroid-cancer/354672/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/convergent-mechanistic-pathways-driving-the-anaplastic-phenotype-in-thyroid-cancer/354672.png","ImageObject",300,407,{"name":92,"@type":93},"LangkahRina","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":8},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why does anaplastic thyroid carcinoma (ATC) not have a universal driver mutation?","Question",{"text":112,"@type":113},"ATC often involves many oncogenic pathways but lacks a single obligate driver mutation. Its pathogenesis is better understood as convergence on shared biological hallmarks rather than dependence on one molecular event.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What mechanistic programs define the ATC phenotype in the review?",{"text":117,"@type":113},"The review highlights disruption of cell-cycle and apoptosis control (including TP53 and CDKN2A/B alterations and aberrant MAPK activation), metabolic adaptations, reprogramming of stress response pathways such as ER stress and hypoxia signaling, and dynamic remodeling of the tumor microenvironment through cytokine-driven paracrine networks and immune modulation.",{"name":119,"@type":110,"acceptedAnswer":120},"How do tumor microenvironment changes contribute to ATC behavior?",{"text":121,"@type":113},"The review describes cytokine-driven paracrine networks and immune modulation that create a tumor state characterized as immune-inflamed yet immunosuppressed. 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DeSouza 1, Nan Yang 2, Shaun Desai 3, Augustine Moscatello 3, David Garber 3, Steven Hemmerdinger 3, Janine M. Rotsides 3, Mike Yao 3, Raj K. Tiwari 1,3, Jan Geliebter 1,3, *  \nand Xiu-Min Li 1,3,4, *  \nAcademic Editor: Kurt A. Jellinger  \nReceived: 28 May 2026  \nRevised: 6 July 2026  \nAccepted: 22 July 2026  \nPublished: 10 August 2026  \nCopyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \n1 Department of Pathology, Microbiology & Immunology, New York Medical College, Valhalla, NY 10595, USA; [acentone@nymc.edu](acentone@nymc.edu) (A.C.)  \n2 Division of R&D, General Nutraceutical Technology, LLC., Briarcliff Manor, NY 10510, USA  \n3 Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA  \n4 Department of Dermatology, New York Medical College, Valhalla, NY 10595, USA  \n* [Correspondence: jan_geliebter@nymc.edu](Correspondence: jan_geliebter@nymc.edu) (J.G.); [xiumin_li@nymc.edu](xiumin_li@nymc.edu) (X.-M.L.)  \nAbstract  \nAnaplastic 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 alterationsin 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 generatea 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.  \nKeywords: anaplastic thyroid cancer; tumor microenvironment; metabolic reprogramming; hypoxia signaling; ER stress  \n1. Introduction  \nAnaplastic thyroid carcinoma (ATC) represents the most aggressive and lethal form of thyroid cancer. Arising from thyroid follicular cells, ATC is classified by its progressive loss of follicular cell differentiation and acquisition of a highly proliferative, invasive, and therapy-resistant phenotype. Although ATC accounts for a minority of thyroid cancer cases, its disproportionately high mortality underscores a critical need for a deeper understanding of its dynamic oncogenic nature. Unlike differentiated thyroid cancers, which often remain driven by core targetable oncogenic events, ATC lacks a single obligate driver mutation and instead reflects a convergence of genetic, metabolic, stress-adaptive, and microenvironmental alterations that collectively reinforce its aggressive state. Accordingly, ATC should be conceptualized not as the product of a singular linear pathway, but rather  \nas a convergent endpoint reached through multiple distinct molecular and cellular actions. This review summarizes the current evidence and the core biological processes that define ATC, including loss of cell-cycle and apoptotic control, metabolic reprogramming, stress adaptation, and tumor microenvironment (TME) remodeling. It further examines how diverse molecular alterations converge to sustain these shared malignant programs.","cbCainzbwcHuCL8M","https://ap.wps.com/l/cbCainzbwcHuCL8M","pdf",2747216,21,"English","# Abstract\n# 1. Introduction\n## 1.1. Thyroid Structure and Function\n## 1.2. Anaplastic Thyroid Cancer","[{\"question\":\"Why does anaplastic thyroid carcinoma (ATC) not have a universal driver mutation?\",\"answer\":\"ATC often involves many oncogenic pathways but lacks a single obligate driver mutation. Its pathogenesis is better understood as convergence on shared biological hallmarks rather than dependence on one molecular event.\"},{\"question\":\"What mechanistic programs define the ATC phenotype in the review?\",\"answer\":\"The review highlights disruption of cell-cycle and apoptosis control (including TP53 and CDKN2A/B alterations and aberrant MAPK activation), metabolic adaptations, reprogramming of stress response pathways such as ER stress and hypoxia signaling, and dynamic remodeling of the tumor microenvironment through cytokine-driven paracrine networks and immune modulation.\"},{\"question\":\"How do tumor microenvironment changes contribute to ATC behavior?\",\"answer\":\"The review describes cytokine-driven paracrine networks and immune modulation that create a tumor state characterized as immune-inflamed yet immunosuppressed. This remodeling supports aggressive growth and therapy resistance.\"}]","Convergent Mechanistic Pathways Driving the Anaplastic Phenotype in Thyroid Cancer | PDF",1790112878,53]