DataSheet_1_IP-10 (CXCL10) Can Trigger Emergence of Dormant Breast Cancer Cells in a Metastatic Liver Microenvironment.docx

Metastatic breast cancer remains a largely incurable and fatal disease with liver involvement bearing the worst prognosis. The danger is compounded by a subset of disseminated tumor cells that may lie dormant for years to decades before re-emerging as clinically detectable metastases. Pathophysiological signals can drive these tumor cells to emerge. Prior studies indicated CXCR3 ligands as being the predominant signals synergistically and significantly unregulated during inflammation in the gut-liver axis. Of the CXCR3 ligands, IP-10 (CXCL10) was the most abundant, correlated significantly with shortened survival of human breast cancer patients with metastatic disease and was highest in those with triple negative (TNBC) disease. Using a complex ex vivo all-human liver microphysiological (MPS) model of dormant-emergent metastatic progression, CXCR3 ligands were found to be elevated in actively growing populations of metastatic TNBC breast cancer cells whereas they remained similar to the tumor-free hepatic niche in those with dormant breast cancer cells. Subsequent stimulation of dormant breast cancer cells in the ex vivo metastatic liver MPS model with IP-10 triggered their emergence in a dose-dependent manner. Emergence was indicated to occur indirectly possibly via activation of the resident liver cells in the surrounding metastatic microenvironment, as stimulation of breast cancer cells with exogenous IP-10 did not significantly change their migratory, invasive or proliferative behavior. The findings reveal that IP-10 is capable of triggering the emergence of dormant breast cancer cells within the liver metastatic niche and identifies the IP-10/CXCR3 as a candidate targetable pathway for rational approaches aimed at maintaining dormancy.

转移性乳腺癌作为一种主要难以治愈且致命的疾病，其肝脏受累情况更预示着最差的预后。危险因素进一步加剧，由于部分散播的肿瘤细胞可能在数年至数十年间处于休眠状态，而后再次出现并形成临床可检测的转移。病理生理信号可以驱动这些肿瘤细胞重新活跃。先前的研究指出，在肠道-肝脏轴的炎症过程中，CXCR3配体作为主要的协同且显著未受调节的信号。在CXCR3配体中，IP-10（CXCL10）最为丰富，其与人类乳腺癌患者转移性疾病的生存期缩短具有显著相关性，且在具有三阴性（TNBC）疾病的患者中含量最高。利用一种复杂的原位外源性全人类肝脏微生理学（MPS）模型，观察到在活跃生长的转移性TNBC乳腺癌细胞群体中CXCR3配体水平升高，而在休眠乳腺癌细胞的肿瘤无肝生态位中则保持相似。随后，在原位外源性转移性肝脏MPS模型中对休眠的乳腺癌细胞进行IP-10刺激，以剂量依赖性方式触发其活跃。活跃的出现被认为是间接发生的，可能通过激活周围转移性微环境中的驻留肝脏细胞实现，因为使用外源性IP-10刺激乳腺癌细胞并未显著改变其迁移、侵袭或增殖行为。这些发现揭示了IP-10能够触发肝脏转移生态位中休眠乳腺癌细胞的活跃，并确定了IP-10/CXCR3作为维持休眠状态的理性策略的可靶向通路。