Decoding the role of cadherin 11 in early cancer dissemination, dormancy and metastatic reactivation

癌症在全身扩散，称为转移，是与癌症相关的死亡的90%的原因。尽管癌症扩散的复杂性，但有越来越多的证据表明，癌细胞在癌症进化的早期就离开了原发部位(例如原位状态)。这些早期播散性肿瘤细胞(EDTC)寄居在次级器官中，在那里它们通常会保持数年至数十年的沉默，这一过程被称为休眠。然而，DTCs可以重新激活增殖程序，并导致晚期转移复发。该项目的目的是破译乳腺癌早期扩散和休眠的机制，特别是黏附蛋白钙粘蛋白11(CDH11)对功能的影响。我们的初步数据表明，CDH11在早期HER2+乳腺癌中具有促进侵袭/扩散和抗增殖的作用。因此，我们认为CDH11在癌前早期病变的扩散以及eDTC在骨髓(BM)、肝脏和肺的休眠中起作用。深入研究CDH11在体外和体内的表达动态，利用3D有机物培养、可诱导基因敲除(KO)系统、单细胞测序以及CDH11报告小鼠和活体成像，将有助于破译CDH11在乳腺癌休眠和转移再激活过程中的不同功能。我们还旨在确定CDH11阳性或阴性DTCs的生态位成分，它们可能介导癌细胞休眠或转移重新激活。在详细了解CDH11的调控和信号转导的基础上，我们的目标是开发针对乳腺癌休眠和晚期复发的策略。

The spread of cancer throughout the body, termed metastasis, is responsible for 90% of cancer-related deaths. Despite the complexity of cancer dissemination, there is increasing evidence for cancer cells leaving the primary site very early in cancer evolution (e.g. in-situ state). These early disseminated tumor cells (eDTCs) lodge in secondary organs, where they often remain silent for years to decades, a process called dormancy. However, DTCs can re-activate proliferative programs and cause late metastatic relapse. The aim of this project is to decode the mechanism of early dissemination and breast cancer dormancy, with a special emphasis on the functional influence of the adhesion protein cadherin 11 (CDH11). Our preliminary data suggests a pro-invasive/disseminating and anti-proliferative role of CDH11 in early HER2+ breast cancer. Hence, we suggest a role of CDH11 in dissemination of pre-malignant early lesions, as well as eDTC dormancy in the bone marrow (BM), liver and lung. In depth studies of the expression dynamics in vitro and in vivo, exploiting 3D organoid culture, inducible knockout (KO) systems, single cell sequencing, as well as a CDH11-reporter mouse and intravital imaging will allow to decipher distinct functional roles of CDH11 during dormancy and metastatic reactivation of breast cancer. We also aim to determine niche components of CDH11 positive or negative DTCs, which may mediate cancer cell dormancy or metastatic reactivation. On the basis of detailed understanding of the regulation and signaling of CDH11, we aim to develop strategies to specifically target dormancy and late recurrence of breast cancer.