Interactions between mutant cells and their environment have a key role in determining cancer susceptibility1,2,3. However, understanding of how the precancerous microenvironment contributes to early tumorigenesis remains limited. Here we show that newly emerging tumours at their most incipient stages shape their microenvironment in a critical process that determines their survival. Analysis of nascent squamous tumours in the upper gastrointestinal tract of the mouse reveals that the stress response of early tumour cells instructs the underlying mesenchyme to form a supportive ‘precancerous niche’, which dictates the long-term outcome of epithelial lesions. Stimulated fibroblasts beneath emerging tumours activate a wound-healing response that triggers a marked remodelling of the underlying extracellular matrix, resulting in the formation of a fibronectin-rich stromal scaffold that promotes tumour growth. Functional heterotypic 3D culture assays and in vivo grafting experiments, combining carcinogen-free healthy epithelium and tumour-derived stroma, demonstrate that the precancerous niche alone is sufficient to confer tumour properties to normal epithelial cells. We propose a model in which both mutations and the stromal response to genetic stress together define the likelihood of early tumours to persist and progress towards more advanced disease stages.
突变细胞与其环境之间的相互作用在决定癌症易感性方面起着关键作用¹⁻³。然而，人们对癌前微环境如何促进早期肿瘤发生的了解仍然有限。在此，我们展示了新出现的肿瘤在最初始阶段通过一个关键过程塑造其微环境，从而决定其生存。对小鼠上消化道新生鳞状肿瘤的分析表明，早期肿瘤细胞的应激反应会诱导下方的间质形成支持性的"癌前生态位"，这决定了上皮病变的长期结局。新生肿瘤下方的受激成纤维细胞激活伤口愈合反应，触发下方细胞外基质的显著重塑，形成富含纤连蛋白的基质支架，从而促进肿瘤生长。结合无致癌物健康上皮和肿瘤来源基质的功能性异型3D培养实验和体内移植实验证明，仅凭癌前生态位就足以赋予正常上皮细胞肿瘤特性。我们提出的模型表明，突变和基质对遗传应激的反应共同决定了早期肿瘤持续存在并进展至更晚期疾病阶段的可能性。
Precancerous niche remodelling dictates nascent tumour persistence
肿瘤(癌症)患者之家