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

癌症在全身的扩散，称为转移，是90%癌症相关死亡的原因。尽管癌症传播的复杂性，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）。这些早期弥散性肿瘤细胞（edtc）寄居在次要器官中，它们通常在那里沉默数年至数十年，这一过程被称为休眠。然而，dtc可以重新激活增殖程序并引起晚期转移性复发。本项目旨在解码乳腺癌早期传播和休眠的机制，特别强调粘附蛋白cadherin 11 （CDH11）的功能影响。我们的初步数据表明，CDH11在早期HER2+乳腺癌中具有促进侵袭/传播和抗增殖的作用。因此，我们认为CDH11在恶性前期早期病变的传播以及eDTC在骨髓、肝脏和肺部的休眠中发挥了作用。通过对体外和体内表达动态的深入研究，利用3D类器官培养、诱导敲除（KO）系统、单细胞测序以及CDH11报告小鼠和活体成像，将能够解读CDH11在乳腺癌休眠和转移性再激活过程中的不同功能作用。我们还旨在确定CDH11阳性或阴性dtc的生态位成分，这些成分可能介导癌细胞休眠或转移性再激活。在详细了解CDH11的调控和信号传导的基础上，我们的目标是制定针对乳腺癌休眠和晚期复发的特异性策略。

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.