所有癌症起源于正常细胞，其后代获得了引发癌症的突变和表观遗传修饰，导致明显的肿瘤发生。"起源细胞"的身份在肿瘤类型间一直是一个有争议的问题，因为我们无法观察到形成人类肿瘤的动态过程。癌症的基因工程小鼠模型（GEMMs）提供了宝贵的替代方法，使研究人员能够探索各种未经训练的细胞区域在体内引发肿瘤的能力。使用这些模型的研究人员依赖于特定谱系的启动子、对人类癌前病态的了解以及允许更精确操作小鼠生殖系的技术进步。这些方法产生了新兴观点，即在给定器官中的多个谱系可能会产生具有相似组织病理学的肿瘤。在这里，我们回顾了一些在实体瘤中导致这一结论的关键研究，同时强调了生物学和临床的关联。版权所有©2023冷泉港实验室出版社；保留一切权利。

All cancers arise from normal cells whose progeny acquire the cancer-initiating mutations and epigenetic modifications leading to frank tumorigenesis. The identity of those "cells-of-origin" has historically been a source of controversy across tumor types, as it has not been possible to witness the dynamic events giving rise to human tumors. Genetically engineered mouse models (GEMMs) of cancer provide an invaluable substitute, enabling researchers to interrogate the competence of various naive cellular compartments to initiate tumors in vivo. Researchers using these models have relied on lineage-specific promoters, knowledge of preneoplastic disease states in humans, and technical advances allowing more precise manipulations of the mouse germline. These approaches have given rise to the emerging view that multiple lineages within a given organ may generate tumors with similar histopathology. Here, we review some of the key studies leading to this conclusion in solid tumors and highlight the biological and clinical ramifications.Copyright © 2023 Cold Spring Harbor Laboratory Press; all rights reserved.