Mechanisms of early metastatic spread: Epigenetic plasticity and selection of advantageous genotypes

分析Balb/Neut小鼠乳腺癌模型，我们发现癌细胞的转移性扩散发生在恶性转化后不久。在转基因诱导1-4周后，我们在肺和骨髓中检测到播散性肿瘤细胞(DTC)。令人惊讶的是，在肉眼或微观肿瘤被发现之前，DTC就在骨髓中被发现了。无论是在小鼠还是在患者身上，都没有观察到随着原发肿瘤大小的增加，骨髓中的DTCs增加。首先，分子研究揭示了早期病变中蛋白水解酶和转录因子Twist的上调，甚至超过了在大型癌症侵袭前沿可检测到的水平。在拟议的项目中，我们希望使用Balb/Neut模型和我们的合作者的其他四个小鼠模型来识别早期癌症扩散的分子机制。候选监管者将在人体样本上进行测试。我们项目的核心是试图准确地识别侵袭和扩散的肿瘤细胞，并提供其表型和基因的详细描述。功能分析将测试候选监管机构。我们还将询问，在散发性肿瘤中发现的癌症扩散的生理机制是否不同于目前提出的大多数在细胞系中发现的机制，这意味着转移扩散是一种晚期事件。

Analysing the Balb/NeuT mouse model of breast cancer, we found that metastatic dissemination of cancer cells takes place shortly after malignant transformation. Already one to four 4 weeks after induction of the transgene, we detected disseminated tumour cells (DTC) in lung and bone marrow. Surprisingly, DTCs were found in bone marrow before macroscopic or microscopic tumours were detectable. No increase of DTCs in bone marrow was observed with increasing size of the primary tumours neither in mice nor in patients. First molecular studies revealed an upregulation of proteolytic enzymes and of the transcription factor Twist in early lesions that even exceeded the levels detectable in the invasion front of large carcinomas. In the proposed project we want to use the Balb/NeuT model and four other mouse models of our collaborators to identify the molecular mechanisms of early cancer spread. Candidate regulators will be tested on human samples. Central to our project is the attempt to precisely identify the invading and disseminating tumour cells and to provide a detailed description of their phenotype and genotype. Functional assays will test candidate regulators. We will also ask whether the physiological mechanisms of cancer spread seen in sporadically arising tumours are different to currently proposed mechanisms mostly identified in cell lines, which imply that metastatic dissemination is a late event.