Development of functional models for micrometastasis research: Linking descriptive characteristics of disseminated cancer cells to functional properties

DFG/NWO内部的这种合作最初是为了检测早期播散性肿瘤细胞（DTC）中的遗传改变而建立的，这些遗传改变表明这些细胞的恶性来源，可能使转移性复发的风险分层成为可能，并可以表征推定的转移性干细胞。从我们自己最近的工作和其他小组的工作来看，不成熟的乳腺癌细胞（即，不具有在成熟原发性肿瘤中发现的所有遗传改变的细胞）已经可以通过血液扩散到次级器官（特别是骨髓），在新的微环境中存活，并最终发展为独立于原发性肿瘤的明显转移性病变。因此，肿瘤细胞播散可能是乳腺癌发展的早期事件，而在头颈癌中，它似乎是淋巴结转移成功建立后的晚期事件。在第二个资助期，我们将通过比较骨髓中的DTC与同一患者原发部位或淋巴结中的自体肿瘤细胞来研究这一具有挑战性的概念，使用乳腺癌和头颈癌作为具有相反转移行为的上皮肿瘤。为了将DTC的描述性特征与其功能特性联系起来，将建立细胞系并用作模型。该项目的发现可能为DTC的生物学提供新的见解，并对旨在消除这些细胞以防止明显转移的治疗方法产生影响。

This collaboration within DFG/NWO was initially established to detect genetic alterations in early disseminated tumor cells (DTC) that indicate the malignant source of these cells, might enable risk stratification for metastatic relapse and could characterize putative metastatic stem cells. From our own recent work and that of other groups the picture emerged that immature breast cancer cells (i.e., cells not having all the genetic alterations that are found in the mature primary tumor) can already disseminate via the blood to secondary organs (in particular bone marrow), survive in the new microenvironment and eventually progress to overt metastatic lesions independent from the primary tumor. Thus, tumor cell dissemination can be a very early event in breast cancer development, whereas in head and neck cancer it seems to be a later event following successful establishment of lymph node metastases. In the second funding period we will investigate this challenging concept by comparing DTC in bone marrow with autologous tumor cells at the primary site or in lymph nodes from the same patient, using breast and head and neck cancer as epithelial tumors with opposing metastatic behavior. To link the descriptive characteristics of DTC to their functional properties, cell lines will be established and used as models. The findings of this project may provide new insights into the biology of DTC with implications for therapeutic approaches aimed to eliminate these cells in order to prevent overt metastasis.