Institut de Génétique Moléculaire de Montpellier, University of Montpellier, Montpellier, France.
Department of surgery and liver transplantation, Hopital Saint Eloi Hopitaux universitaires de Montpelier, Montpellier, France.
Elife. 2023 Jan 19;12:e76294. doi: 10.7554/eLife.76294.
Quantitative differences in signal transduction are to date an understudied feature of tumour heterogeneity. The MAPK Erk pathway, which is activated in a large proportion of human tumours, is a prototypic example of distinct cell fates being driven by signal intensity. We have used primary hepatocyte precursors transformed with different dosages of an oncogenic form of Ras to model subclonal variations in MAPK signalling. Orthotopic allografts of Ras-transformed cells in immunocompromised mice gave rise to fast-growing aggressive tumours, both at the primary location and in the peritoneal cavity. Fluorescent labelling of cells expressing different oncogene levels, and consequently varying levels of MAPK Erk activation, highlighted the selection processes operating at the two sites of tumour growth. Indeed, significantly higher Ras expression was observed in primary as compared to secondary, metastatic sites, despite the apparent evolutionary trade-off of increased apoptotic death in the liver that correlated with high Ras dosage. Analysis of the immune tumour microenvironment at the two locations suggests that fast peritoneal tumour growth in the immunocompromised setting is abrogated in immunocompetent animals due to efficient antigen presentation by peritoneal dendritic cells. Furthermore, our data indicate that, in contrast to the metastatic-like outgrowth, strong MAPK signalling is required in the primary liver tumours to resist elimination by NK (natural killer) cells. Overall, this study describes a quantitative aspect of tumour heterogeneity and points to a potential vulnerability of a subtype of hepatocellular carcinoma as a function of MAPK Erk signalling intensity.
迄今为止，信号转导的定量差异是肿瘤异质性研究不足的一个特征。MAPK Erk 途径在很大比例的人类肿瘤中被激活，是信号强度驱动不同细胞命运的典型例子。我们使用不同剂量的致癌形式 Ras 转化的原代肝细胞前体来模拟 MAPK 信号转导中的亚克隆变化。在免疫功能低下的小鼠中，将 Ras 转化的细胞原位移植会导致快速生长的侵袭性肿瘤，无论是在原发部位还是在腹腔内。表达不同致癌基因水平的细胞（因此 MAPK Erk 激活水平也不同）的荧光标记突出了在肿瘤生长的两个部位起作用的选择过程。事实上，与 secondary（继发的）和 metastatic（转移性的）部位相比，primary（原发的）部位的 Ras 表达明显更高，尽管在与高 Ras 剂量相关的肝脏中明显增加的凋亡死亡存在明显的进化权衡。对两个部位的免疫肿瘤微环境的分析表明，在免疫功能正常的动物中，由于腹腔树突状细胞的有效抗原呈递，免疫缺陷小鼠中快速的腹膜肿瘤生长在免疫功能正常的环境中被阻断。此外，我们的数据表明，与转移性生长相反，在原发性肝肿瘤中强烈的 MAPK 信号对于抵抗 NK（自然杀伤）细胞的消除是必需的。总的来说，这项研究描述了肿瘤异质性的一个定量方面，并指出了一种肝癌亚型作为 MAPK Erk 信号强度的功能的潜在脆弱性。
