Data from: Aberrant activation of the RANK signaling receptor induces murine salivary gland tumors

Unlike cancers of related exocrine tissues such as the mammary and prostate gland, diagnosis and treatment of aggressive salivary gland malignancies have not markedly advanced in decades. Effective clinical management of malignant salivary gland cancers is undercut by our limited knowledge concerning the key molecular signals that underpin the etiopathogenesis of this rare and heterogeneous head and neck cancer. Without knowledge of the critical signals that drive salivary gland tumorigenesis, tumor vulnerabilities cannot be exploited that allow for targeted molecular therapies. This knowledge insufficiency is further exacerbated by a paucity of preclinical mouse models (as compared to other cancer fields) with which to both study salivary gland pathobiology and test novel intervention strategies. Using a mouse transgenic approach, we demonstrate that deregulation of the Receptor Activator of NFkB Ligand (RANKL)/RANK signaling axis results in rapid tumor development in all three major salivary glands. In line with its established role in other exocrine gland cancers (i.e., breast cancer), the RANKL/RANK signaling axis elicits an aggressive salivary gland tumor phenotype both at the histologic and molecular level. Despite the ability of this cytokine signaling axis to drive advanced stage disease within a short latency period, early blockade of RANKL/RANK signaling markedly attenuates the development of malignant salivary gland neoplasms. Together, our findings have uncovered a tumorigenic role for RANKL/RANK in the salivary gland and suggest that targeting this pathway may represent a novel therapeutic intervention approach in the prevention and/or treatment of this understudied head and neck cancer.与乳腺（mammary gland）、前列腺（prostate gland）等相关外分泌组织（exocrine tissues）的癌症不同，侵袭性唾液腺恶性肿瘤（salivary gland malignancies）的诊断与治疗在数十年来并未取得显著进展。恶性唾液腺肿瘤的有效临床管理受到削弱，原因在于我们对这种罕见且异质性头颈癌（head and neck cancer）的发病机制（etiopathogenesis）所依赖的关键分子信号的认知不足。若缺乏驱动唾液腺肿瘤发生（tumorigenesis）的关键信号相关知识，便无法挖掘肿瘤脆弱靶点（tumor vulnerabilities）以开发靶向分子疗法。此外，相较于其他癌症研究领域，当前用于研究唾液腺病理生物学、测试新型干预策略的临床前小鼠模型（preclinical mouse models）极为匮乏，进一步加剧了这种知识缺口。本研究通过转基因小鼠模型证实，核因子κB受体激活剂配体（Receptor Activator of NFkB Ligand, RANKL）/核因子κB受体激活剂（RANK）信号轴（signaling axis）的失调，可诱导三大主要唾液腺快速发生肿瘤。正如其在其他外分泌腺癌症（如乳腺癌）中的既定作用一致，RANKL/RANK信号轴在组织学（histologic）与分子层面均诱导出侵袭性唾液腺肿瘤表型。尽管该细胞因子信号轴（cytokine signaling axis）可在短潜伏期（latency period）内驱动疾病进展至晚期，但早期阻断RANKL/RANK信号通路可显著抑制恶性唾液腺肿瘤（neoplasms）的发生发展。综上，本研究揭示了RANKL/RANK信号轴在唾液腺中的致癌作用，并提示靶向该通路或可成为预防和/或治疗这种长期未被充分研究的头颈癌的新型干预手段。