The origin and fate of cancer cells touch every aspect of biology, from the genetic scale to the organism's multicellular organisation and its relationship with the environment. From cells and their microenvironment to their harbouring organism and its environment, tumour progression is, by all means, an evolutionary phenomenon. Nordling^[1] was one of the first taking a step towards evolution in cancer, originating the notion of cancer onset as a multi-stage accumulation of mutations. That process entails transforming a cell from a healthy phenotype towards a cancer one resulting from a collection of mutations, which sooner or later co-emerge with the local microenvironment, reproducing the well-known cancer hallmarks.^[2] How that complex process is triggered and evolves remains a puzzle. However, any approach should consider the mechanistic integration between evolutionary history and the myriad hallmarks of cancer plus the interaction between genes and the immediate tumour microenvironment as essential ingredients for evolution.

In this issue, Lineweaver and colleagues^[3] contribute to filling the gap. They propose a novel hypothesis that moves one step forward the atavistic model of cancer, that is, the idea that cancer in multicellular organisms resembles an atavistic cellular machinery characteristic of ancestral unicellular organisms. Their model, named the Serial Atavism Model, presents the idea that cancer progression is not a one-shot reversion towards a quasi-unicellular state of cells; instead, it emerges from a series of ordered steps that erode the multicellular organisation of metazoans. The authors invite us to embrace their disruptive and novel idea and to think of tumour progression as an ordered and regular phenomenon across species and cancer types. They hypothesise that the sequence of changes from a healthy phenotype to cancer and its further evolution may follow a similar trajectory but in a reverse direction relative to the transition from single-cell organisms to multicellularity. They also extend their model to reaching eukaryogenesis, oxidative phosphorylation and the transition to adaptive immunity.

The new proposal made by Lineweaver et al. is thought-provoking, and it is worthy of attention and evaluation. However, a serial steps consideration such as theirs constrains the possible evolutionary trajectories towards hallmarks deeply encrypted in the evolutionary history. But, their perspective fires up new questions. For example, do cancer cells find short-cuts in their evolution towards hallmarks that, despite an ancient origin, present adaptive advantages in the local context, or are they prisoners of their evolutionary history? How does this hypothesis explain the emergence of tumour heterogeneity? And how is that linked to the dynamic local environment or local ecology?^[4] Further efforts need to consider that the order of events (intra or extracellular) matters in cancer evolution.^[5] Although the authors did not intend to answer these fundamental questions, their hypothesis and suggested evaluation could point to that direction deserving further testing; above all, because, through the understanding of the fundamental process of tumour progression, we move the frontier of the unknown to gain clarity to improve patients’ survival.

This article comments on the hypothesis paper by Charles H. Lineweaver et al., https://doi.org/10.1002/bies.202000305

癌细胞的起源和命运涉及生物学的方方面面，从遗传尺度到生物体的多细胞组织及其与环境的关系。从细胞及其微环境到其栖息的生物体及其环境，肿瘤进展无论如何都是一种进化现象。Nordling ^{[ 1 ]}是第一个朝着癌症进化迈出一步的人之一，他提出了癌症发病是多阶段突变积累的概念。该过程需要将细胞从健康表型转变为由一系列突变引起的癌症，这些突变迟早会与局部微环境共同出现，再现众所周知的癌症特征。^{[ 2 ]}这个复杂的过程如何被触发和演变仍然是一个谜。然而，任何方法都应考虑进化历史与无数癌症特征之间的机制整合，以及基因与直接肿瘤微环境之间的相互作用，作为进化的基本要素。

在本期中，Lineweaver 及其同事^{[ 3 ]}有助于填补空白。他们提出了一个新的假设，使癌症的返祖模型向前迈进了一步，即多细胞生物中的癌症类似于祖先单细胞生物的返祖细胞机制。他们的模型被命名为串行返祖模型，它提出了这样一种观点，即癌症的进展不是一次性逆转为细胞的准单细胞状态。相反，它是从一系列有序的步骤中产生的，这些步骤侵蚀了后生动物的多细胞组织。作者邀请我们接受他们的颠覆性和新颖的想法，并将肿瘤进展视为跨物种和癌症类型的有序且规律的现象。他们假设从健康表型到癌症的变化序列及其进一步进化可能遵循类似的轨迹，但与从单细胞生物到多细胞生物的转变方向相反。他们还将他们的模型扩展到实现真核发生、氧化磷酸化和向适应性免疫的过渡。

Lineweaver 等人提出的新建议。发人深省，值得关注和评价。然而，像他们这样的连续步骤考虑将可能的进化轨迹限制在进化历史中深度加密的标志上。但是，他们的观点引发了新的问题。例如，癌细胞是否在其进化过程中找到了捷径，尽管起源古老，但在当地环境中具有适应性优势，还是它们被进化史所束缚？这个假设如何解释肿瘤异质性的出现？这与动态的当地环境或当地生态有何联系？^{[ 4 ]}进一步的努力需要考虑事件（细胞内或细胞外）的顺序在癌症进化中很重要。^{[ 5 ]}尽管作者并不打算回答这些基本问题，但他们的假设和建议的评估可能指向值得进一步测试的方向；最重要的是，因为通过了解肿瘤进展的基本过程，我们移动了未知的前沿，以提高患者的生存率。

本文评论了 Charles H. Lineweaver 等人的假设论文，https://doi.org/10.1002/bies.202000305