乌得勒支大学Hugo J. G. Snippert小组的研究显示，癌胚可塑性在早期结直肠癌中普遍存在。2026年4月15日出版的《自然》发表了这项成果。

在这里，该课题组发现转移相关的癌胎细胞状态已经出现在结直肠癌的早期阶段，与浸润性癌前形成同时发生。

然而，尽管它们是转移所必需的，但课题组人员在早期非转移性癌症中普遍发现它们，突出了额外的瓶颈，如免疫逃避。为了了解癌胎细胞最初是如何出现的，该课题组人员建立了多区域类器官模型，反映了个体早期结直肠癌中连续的肿瘤进展阶段。全基因组测序和生长因子依赖性测定排除肿瘤细胞固有的获得性特征。相比之下，恶性转化前后肿瘤微环境的单细胞空间图谱显示成纤维细胞亚型类似于正常组织结构的刻板模式，导致不同的区域微环境。

在恶性肿瘤向粘膜下层生长时，第一个与癌症相关的成纤维细胞表现出与粘膜下滋养细胞非常相似的特征，并在侵袭前沿与癌胎细胞状态共定位。功能上，成纤维细胞-类器官共培养证实了这些滋养细胞样癌症相关成纤维细胞诱导可塑过渡到癌胎状态。因此，恶性转化后肿瘤和粘膜下成纤维细胞之间的相互作用决定了结直肠癌进展过程中癌胎可塑性首次发生的时间和位置。

据悉，转移形成通常被认为是结直肠癌发展的晚期事件。然而，转移能力获得的时间和空间模式仍然知之甚少。

附：英文原文

Title: Emergence of oncofetal plasticity is ubiquitous in early colorectal cancers

Author: Buissant des Amorie, Julian R., Hageman, Joris H., Brunner, Sascha R., van der Horst, Suzanne E. M., Puschhof, Maria C., van Hoeck, Arne, van Lierop, Inge, Middelkamp, Sjors, van der Schee, Lisa, van Kempen, Sven, Morsink, Folkert, Geene, Robin, Mertens, Sander, Cavigelli, David S., Verlaan-Klink, Ingrid, Kraaier, Lianne J., Salij, Jorieke, Bezemer, Renate, Kranenburg, Onno, Lacl, Miangela M., Moons, Leon M. G., Snippert, Hugo J. G.

Issue&Volume: 2026-04-15

Abstract: Metastasis formation is classically considered a late-stage event in colorectal cancer evolution. Yet the time and spatial patterning by which metastatic competence is acquired remain poorly understood1,2. Here we show that metastasis-associated oncofetal cell states already emerge at the earliest stages of colorectal cancer, concurrent with invasive front formation. However, although necessary for metastasis, we detect them ubiquitously among early non-metastatic cancers, highlighting extra bottlenecks such as immune evasion. To understand how oncofetal cells first emerge, we generated multiregional organoid models that reflect successive tumour progression stages within individual early-stage colorectal cancers. Whole-genome sequencing and growth factor-dependency assays exclude tumour cell-intrinsic acquired traits. By contrast, single-cell spatial atlases of the tumour microenvironment before and after malignant transformation revealed stereotypic patterning of fibroblast subtypes resembling normal tissue architecture, resulting in distinct regional microenvironments. At the onset of malignant growth into the submucosa, the first cancer-associated fibroblasts to appear strongly resemble submucosal trophocytes and colocalize with oncofetal cell states at invasive fronts. Functionally, fibroblast–organoid cocultures confirm that these trophocyte-like cancer-associated fibroblasts induce plastic transitioning to oncofetal states. Thus, interactions between tumour and submucosal fibroblasts directly following malignant transformation dictate the timing and location at which oncofetal plasticity first occurs during colorectal cancer progression.

DOI: 10.1038/s41586-026-10344-7

Source: https://www.nature.com/articles/s41586-026-10344-7