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Intratumoural heterogeneity (ITH) complicates treatment because different clones and phenotypes coexist and evolve. This review examines how genetic and non-genetic drivers, including tumour microenvironment cues, shape the multicellularity-to-unicellularity transition, promote ITH, and drive cancer evolution. It also surveys new omics tools for single-cell and spatial mapping to identify key evolutionary drivers for targeted therapy.",{"@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":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/decoding-cancer-evolution-integrating-genetic-and-non-genetic-insights/375650/",{"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/decoding-cancer-evolution-integrating-genetic-and-non-genetic-insights/375650.png","ImageObject",300,407,{"name":92,"@type":93},"Oliver","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-28","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How does the review describe the shift that initiates cancer development?","Question",{"text":112,"@type":113},"It describes cancer as beginning when cells transition from their multicellular nature to a unicellular-like state, breaking key multicellularity regulators and enabling diverse cancer cell subpopulations.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Why does intratumoural heterogeneity (ITH) make cancer treatment challenging?",{"text":117,"@type":113},"Because multiple distinct cancer cell subpopulations coexist within a tumour and evolve with enhanced adaptability, making it harder for therapies to target all relevant clones.",{"name":119,"@type":110,"acceptedAnswer":120},"What roles do genetic and non-genetic factors play in cancer evolution and ITH?",{"text":121,"@type":113},"The review highlights that both genetic alterations and non-genetic influences, particularly signals from the tumour microenvironment, promote ITH and shape evolutionary trajectories.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},375650,1790486575,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},8796095461610,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","Review  \nDecoding Cancer Evolution: Integrating Genetic and Non-Genetic Insights  \nArghavan Ashouri 1, Chufan Zhang 2 and Federico Gaiti 1,2, *  \nCitation: Ashouri, A.; Zhang, C.; Gaiti, F. Decoding Cancer Evolution:  \nIntegrating Genetic and Non-Genetic Insights. Genes 2023, 14, 1856 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)genes14101856  \nAcademic Editor: Aurora Nedelcu  \nReceived: 1 September 2023  \nRevised: 19 September 2023  \nAccepted: 22 September 2023  \nPublished: 24 September 2023  \nCopyright: © 2023 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 ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada  \n2 Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada  \n* Correspondence: [federico.gaiti@uhn.ca](federico.gaiti@uhn.ca)  \nAbstract: The development of cancer begins with cells transitioning from their multicellular nature to a state akin to unicellular organisms. This shift leads to a breakdown in the crucial regulators inherent to multicellularity, resulting in the emergence of diverse cancer cell subpopulations that have enhanced adaptability. The presence of different cell subpopulations within a tumour, known as intratumoural heterogeneity (ITH), poses challenges for cancer treatment. In this review, we delve into the dynamics of the shift from multicellularity to unicellularity during cancer onset and progression. We highlight the role of genetic and non-genetic factors, as well as tumour microenvironment, in promoting ITH and cancer evolution. Additionally, we shed light on the latest advancements in omics technologies that allow for in-depth analysis of tumours at the single-cell level and their spatial organization within the tissue. Obtaining such detailed information is crucial for deepening our understanding of the diverse evolutionary paths of cancer, allowing for the development of effective therapies targeting the key drivers of cancer evolution.  \nKeywords: cancer evolution; genetic alterations; epigenetics; tumour heterogeneity; clonal expansions; multicellularity; single cell; phenotype; plasticity; tumour microenvironment  \n1. Introduction  \nCancer is a complex disease characterized by the accumulation of cellular abnormalities over time [1–5] . Throughout the years, several pivotal models have shaped our comprehension of this phenomenon. More than a century ago, Theodor Boveri laid the groundwork for our understanding of the origin of malignant tumours. He postulated that cancers stem from genetic alterations in normal cells and introduced the concept that most tumours and their metastases originate from a single cell, influencing the contemporary notion of clonal expansion [6] . The Armitage and Doll model, established in the 1950s, emphasized the role of multiple genetic changes over time in transforming healthy cells into malignant ones [7] . This model proposed that cancer development is a multistep process characterized by a series of sequential cellular abnormalities, requiring six to seven successive mutations in affected cells. The cumulative impact of mutations on cancer growth was demonstrated in landmark research on retinoblastoma in 1971, motivating the Knudson's “two-hit” concept [8] . In the late 1970s, Peter Nowell pioneered the integration of evolutionary concepts to comprehend cancer's origins and evolution, whereby Darwinian key evolutionary principles (variation, heredity, and selection [9]) were applied to elucidate the mechanisms responsible for cancer formation and development [10] . Nowell's model suggested that most tumours arise from a single neoplastic cell and evolve through a p","cbCaioJlPaWlD8b7","https://ap.wps.com/l/cbCaioJlPaWlD8b7","pdf",1528708,17,"English","# Abstract\n# Keywords\n# 1. Introduction\n## Genetic and evolutionary models of cancer development","[{\"question\":\"How does the review describe the shift that initiates cancer development?\",\"answer\":\"It describes cancer as beginning when cells transition from their multicellular nature to a unicellular-like state, breaking key multicellularity regulators and enabling diverse cancer cell subpopulations.\"},{\"question\":\"Why does intratumoural heterogeneity (ITH) make cancer treatment challenging?\",\"answer\":\"Because multiple distinct cancer cell subpopulations coexist within a tumour and evolve with enhanced adaptability, making it harder for therapies to target all relevant clones.\"},{\"question\":\"What roles do genetic and non-genetic factors play in cancer evolution and ITH?\",\"answer\":\"The review highlights that both genetic alterations and non-genetic influences, particularly signals from the tumour microenvironment, promote ITH and shape evolutionary trajectories.\"}]","Decoding Cancer Evolution - Integrating Genetic and Non-Genetic Insights | PDF",1790215651,43]