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.
转移形成通常被认为是结直肠癌演进过程中的晚期事件。然而，转移能力获得的时间和空间模式仍不清楚。本研究表明，转移相关的癌胚细胞状态在结直肠癌最早阶段就已出现，与侵袭前沿的形成同步。尽管这种状态对转移是必需的，但我们在早期非转移性癌症中普遍检测到它，这凸显了免疫逃逸等其他瓶颈的存在。为了解癌胚细胞最初如何出现，我们建立了多区域类器官模型，这些模型反映了单个早期结直肠癌内连续的肿瘤进展阶段。全基因组测序和生长因子依赖性实验排除了肿瘤细胞内在获得性特征。相反，恶性转化前后肿瘤微环境的单细胞空间图谱显示，成纤维细胞亚型呈现出类似正常组织结构的模式化分布，从而形成独特的区域性微环境。当恶性生长侵入黏膜下层时，最早出现的癌症相关成纤维细胞与黏膜下层营养细胞高度相似，并在侵袭前沿与癌胚细胞状态共定位。功能上，成纤维细胞-类器官共培养实验证实，这些营养细胞样癌症相关成纤维细胞可诱导细胞可塑性转变为癌胚状态。因此，恶性转化后肿瘤细胞与黏膜下层成纤维细胞的相互作用，决定了结直肠癌进展过程中癌胚可塑性首次出现的时间和位置。
Emergence of oncofetal plasticity is ubiquitous in early colorectal cancers
肿瘤(癌症)患者之家