Olmeda David, Cerezo-Wallis Daniela, Riveiro-Falkenbach Erica, Pennacchi Paula C, Contreras-Alcalde Marta, Ibarz Nuria, Cifdaloz Metehan, Catena Xavier, Calvo Tonantzin G, Cañón Estela, Alonso-Curbelo Direna, Suarez Javier, Osterloh Lisa, Graña Osvaldo, Mulero Francisca, Megías Diego, Cañamero Marta, Martínez-Torrecuadrada Jorge L, Mondal Chandrani, Di Martino Julie, Lora David, Martinez-Corral Inés, Bravo-Cordero J Javier, Muñoz Javier, Puig Susana, Ortiz-Romero Pablo, Rodriguez-Peralto José L, Ortega Sagrario, Soengas María S
Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
Department of Pathology, Medical School, Universidad Complutense, Instituto i+12, Hospital Universitario 12 de Octubre, Madrid 28041, Spain.
Nature. 2017 Jun 28;546(7660):676-680. doi: 10.1038/nature22977.
Cutaneous melanoma is a type of cancer with an inherent potential for lymph node colonization, which is generally preceded by neolymphangiogenesis. However, sentinel lymph node removal does not necessarily extend the overall survival of patients with melanoma. Moreover, lymphatic vessels collapse and become dysfunctional as melanomas progress. Therefore, it is unclear whether (and how) lymphangiogenesis contributes to visceral metastasis. Soluble and vesicle-associated proteins secreted by tumours and/or their stroma have been proposed to condition pre-metastatic sites in patients with melanoma. Still, the identities and prognostic value of lymphangiogenic mediators remain unclear. Moreover, our understanding of lymphangiogenesis (in melanomas and other tumour types) is limited by the paucity of mouse models for live imaging of distal pre-metastatic niches. Injectable lymphatic tracers have been developed, but their limited diffusion precludes whole-body imaging at visceral sites. Vascular endothelial growth factor receptor 3 (VEGFR3) is an attractive 'lymphoreporter' because its expression is strongly downregulated in normal adult lymphatic endothelial cells, but is activated in pathological situations such as inflammation and cancer. Here, we exploit this inducibility of VEGFR3 to engineer mouse melanoma models for whole-body imaging of metastasis generated by human cells, clinical biopsies or endogenously deregulated oncogenic pathways. This strategy revealed early induction of distal pre-metastatic niches uncoupled from lymphangiogenesis at primary lesions. Analyses of the melanoma secretome and validation in clinical specimens showed that the heparin-binding factor midkine is a systemic inducer of neo-lymphangiogenesis that defines patient prognosis. This role of midkine was linked to a paracrine activation of the mTOR pathway in lymphatic endothelial cells. These data support the use of VEGFR3 reporter mice as a 'MetAlert' discovery platform for drivers and inhibitors of metastasis.
皮肤黑色素瘤是一种具有淋巴结转移内在潜力的癌症，通常在新生淋巴管生成之前发生。然而，前哨淋巴结切除并不一定能延长黑色素瘤患者的总生存期。此外，随着黑色素瘤的进展，淋巴管会塌陷并功能失调。因此，尚不清楚淋巴管生成是否（以及如何）促成内脏转移。肿瘤和/或其基质分泌的可溶性和囊泡相关蛋白已被认为可调节黑色素瘤患者的转移前微环境。然而，淋巴管生成介质的身份和预后价值仍不清楚。此外，我们对淋巴管生成（在黑色素瘤和其他肿瘤类型中）的理解受到用于远端转移前微环境活体成像的小鼠模型匮乏的限制。已开发出可注射的淋巴示踪剂，但其扩散有限，无法对内脏部位进行全身成像。血管内皮生长因子受体3（VEGFR3）是一种有吸引力的“淋巴报告分子”，因为其在正常成年淋巴管内皮细胞中表达强烈下调，但在炎症和癌症等病理情况下会被激活。在这里，我们利用VEGFR3的这种可诱导性构建小鼠黑色素瘤模型，用于对由人类细胞、临床活检或内源性失调的致癌途径产生的转移进行全身成像。该策略揭示了原发性病变处远端转移前微环境的早期诱导与淋巴管生成无关。对黑色素瘤分泌组的分析以及在临床标本中的验证表明，肝素结合因子中期因子是新淋巴管生成的全身诱导剂，可定义患者预后。中期因子的这一作用与淋巴管内皮细胞中mTOR途径的旁分泌激活有关。这些数据支持将VEGFR3报告基因小鼠用作转移驱动因子和抑制剂的“转移警报”发现平台。
