Mechanisms associated with organotropic metastasis

摘要 大多数患有实体瘤的癌症患者死于转移性疾病，而向器官扩散是一个未充分研究的问题。 转移方面，迫切需要新的见解。流行的“种子和土壤”概念假定， 在一个遥远的器官（土壤）的许可环境是必要的，以支持生存和生长的潜伏 肿瘤细胞（种子）。建议在非转移性器官中诱导允许的土壤以改变转移途径; 然而，缺乏严格的实验证据和机理分析。我们的初步数据显示 向器官转移不仅仅依赖于允许转移的细胞外基质（ECM） 在次级器官中的重塑和BMDCs，但也由血管内皮细胞连接控制 蛋白质及其维持屏障功能的能力。我们的初步研究表明，内皮屏障引导 转移的向器官扩散。我们对这一提议的中心假设是“血管异质性 在功能上有助于向器官转移。“我们证明了器官特异性血管多样性 在向器官转移中的作用。在这里，我们提出的研究，以解开机制，组织纤维化 影响血管床的器官特异性变化，导致与 乳腺癌我们小组的研究建立了各种新型转基因小鼠模型， 确定了I型胶原（Col 1）的功能作用，这是人体中最丰富的蛋白质，肿瘤 微环境和纤维化组织。我们小组的研究产生了两种新的基因工程 小鼠模型（GEMM）系统。具体而言，KPPF; CollsmaKO（FSF-KrasG 12 D/+; Trp 53 frt/frt; Pdx 1-Flp; Col SMA- Cre; Col 1a 1 loxP/loxP）小鼠模型允许在原位αSMA+成纤维细胞中遗传缺失Col 1 PDAC背景。成纤维细胞中的Col 1缺失加速肿瘤进展和免疫抑制， 导致总生存期缩短。相比之下，KPPC（LSL-KrasG 12 D/+; Trp 53 loxP/loxP; Pdx 1- Cre; Col 1a 1 loxP/loxP）小鼠小鼠模型允许在类似的原位癌细胞中遗传缺失Col 1 PDAC背景。成纤维细胞中的Col 1缺失延迟肿瘤进展并减轻免疫抑制， 从而延长了总体生存期。机制研究表明，成纤维细胞来源的Col 1是正常的Col 1 由α 1和α 2链组成的异源三聚体。相反，癌细胞来源的Col 1是独特的Col 1 同源三聚体仅由β 1链组成。在这项研究中，我们将进一步研究Col 1亚型的影响， （同源三聚体与异源三聚体）对癌细胞侵袭和转移的影响。

ABSTRACT Most cancer patients with solid tumors die of metastatic disease and organotropic spread is an understudied aspect of metastasis, for which new insights are urgently required. The prevailing `seed and soil' concept posits that permissive environment in a distant organ (soil) is necessary to support the survival and growth of lurking tumor cells (seeds). Induction of permissive soil in a non-metastatic organ is proposed to re-route metastasis; however, rigorous experimental evidence and mechanistic analyses are lacking. Our preliminary data suggest organotropic metastasis is not solely dependent on the permissive metastatic extracellular matrix (ECM) remodeling and BMDCs in the secondary organs but is also controlled by the vascular endothelial cell junction proteins and their ability to maintain barrier function. Our preliminary studies suggest endothelial barriers guide organotropic spread of metastasis. Our central hypothesis for this proposal is `vascular heterogeneity functionally contributes to organotropic metastasis.' We demonstrate organ-specific vascular diversity may play a role in organotropic metastasis. Here we propose studies to unravel the mechanisms by which tissue fibrosis influences organ-specific changes in the vascular beds, leading to organotropic metastasis associated with breast cancer. The studies from our group established a variety of novel transgenic mouse models and identified the functional roles of type I collagen (Col1), the most abundant protein in the human body, the tumor microenvironment, and fibrotic tissues. The studies from our group generated two novel genetically engineered mouse model (GEMM) systems. In specific, KPPF;Col1smaKO (FSF-KrasG12D/+;Trp53frt/frt;Pdx1-Flp;SMA- Cre;Col1a1loxP/loxP) mouse model allows genetic deletion of Col1 in αSMA+ fibroblasts in the autochthonous PDAC background. Col1 deletion in fibroblasts accelerates tumor progression and immunosuppression, leading to shortened overall survival. In comparison, KPPC (LSL-KrasG12D/+;Trp53loxP/loxP;Pdx1- Cre;Col1a1loxP/loxP) mice mouse model allows genetic deletion of Col1 in cancer cells in similar autochthonous PDAC background. Col1 deletion in fibroblasts delays tumor progression and alleviates immunosuppression, leading to prolonged overall survival. Mechanistic studies revealed that fibroblast-derived Col1 is normal Col1 heterotrimers composed of 1 and 2 chains. In contrast, cancer cell-derived Col1 is a unique Col1 homotrimers composed of only 1 chains. In this study, we will further examine the effects of Col1 subtypes (homotrimers versus heterotrimers) on cancer cell invasiveness and metastasis.