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、前列腺等相关外分泌组织癌症不同，侵袭性涎腺恶性肿瘤的诊断与治疗数十年来并未取得显著进展。目前我们对这种罕见且具有异质性的头颈癌的致病关键分子信号通路认知有限，这极大制约了恶性涎腺肿瘤的有效临床管理。若未能明确驱动涎腺肿瘤发生的关键信号，则无法发掘肿瘤的可靶向位点以开展靶向分子治疗。相较于其他癌症研究领域，目前用于研究涎腺病理生物学、测试新型干预策略的临床前小鼠模型极为匮乏，这进一步加剧了我们的认知不足。本研究采用转基因小鼠模型，证实NF-κB受体激活因子配体（Receptor Activator of NFkB Ligand, RANKL）/RANK信号轴的失调可导致三大主要涎腺快速发生肿瘤。与该信号通路在其他外分泌腺癌症（如乳腺癌）中的既定作用一致，RANKL/RANK信号轴可在组织学与分子层面诱导侵袭性涎腺肿瘤表型。尽管该细胞因子信号轴可在较短潜伏期内促使疾病进展至晚期，但早期阻断RANKL/RANK信号通路可显著抑制恶性涎腺肿瘤的发生发展。综上，本研究揭示了RANKL/RANK信号轴在涎腺中的致瘤作用，并提示靶向该通路或可为这种研究不足的头颈癌提供全新的预防与/或治疗干预策略。