Joannes Loïc, Dupont Laura, Stock Louis, Arpigny Esther, Hubert Pascale, Ancion Marie, Luyckx Margaux, Abinet Joan, Peng Wen, Calaldo Didier, Noel Agnes, Marichal Thomas, Herfs Michael, Deroanne Christophe, Colige Alain
Laboratory of Connective Tissues Biology, GIGA Institute, University of Liège, Liège, Belgium.
Laboratory of Tumor and Development Biology, GIGA Institute, University of Liège, Liège, Belgium.
Cancer Cell Int. 2025 Jun 23;25(1):229. doi: 10.1186/s12935-025-03880-1.
ADAMTS2 is a metalloproteinase known to be implicated in collagen maturation and regulation of (lymph)angiogenesis. As these properties are likely to alter tumor progression, we aimed to assess the overall impact of ADAMTS2 on cancer development.
Using publicly available human cancer datasets, we found that high expression of ADAMTS2 in primary tumors is associated with poor prognosis across various cancer types. Similar analyses were repeated, but this time using the ratio of ADAMTS2 on COL1A1 expression to take into account potential biases due to the involvement of ADAMTS2 in collagen fibril formation. Remarkably, these data indicate that patients with a high ADAMTS2/COL1A1 ratio exhibit an improved overall survival rate, suggesting that ADAMTS2 may inhibit cancer progression by a mechanism independent of collagen accumulation. This hypothesis was evaluated in vivo using ADAMTS2-KO mice and different tumor models characterized by the absence or presence of tumor collagen accumulation, as in MMTV-PyMT mice which develop spontaneous desmoplastic mammary tumors. In all the models, the growth of primary tumors was strongly increased in ADAMTS2-KO mice versus their wild type counterparts, confirming that ADAMTS2 displays anti-tumor properties. In stark contrast, the spread of lung metastases from mammary tumors was virtually prevented in ADAMTS2-KO mice, showing a dual role of ADAMTS2, either beneficial or detrimental, at different stages of cancer progression. Additional investigations, notably by FACS and single cell sequencing, showed that the effect of ADAMTS2 on primary tumors does not result from a direct effect on cancer cells, but rather from modifications in the intratumor innate immune system which becomes more immunosuppressive in the absence of ADAMTS2.
We have shown that ADAMTS2 suppresses tumor growth by inhibiting the progressive establishment of an immunosuppressive microenvironment. Conversely, its presence allows efficient formation of lung metastases. These data identify ADAMTS2 as a cancer regulator with antagonistic functions, limiting initial progression but promoting efficient metastatic dissemination.
ADAMTS2是一种金属蛋白酶，已知其与胶原蛋白成熟以及（淋巴）血管生成的调节有关。由于这些特性可能会改变肿瘤进展，我们旨在评估ADAMTS2对癌症发展的总体影响。
使用公开可用的人类癌症数据集，我们发现原发性肿瘤中ADAMTS2的高表达与多种癌症类型的不良预后相关。重复了类似的分析，但这次使用ADAMTS2与COL1A1表达的比值，以考虑到由于ADAMTS2参与胶原纤维形成而可能产生的偏差。值得注意的是，这些数据表明ADAMTS2/COL1A1比值高的患者总体生存率提高，这表明ADAMTS2可能通过一种独立于胶原蛋白积累的机制抑制癌症进展。使用ADAMTS2基因敲除小鼠和不同的肿瘤模型在体内评估了这一假设，这些模型的特征是存在或不存在肿瘤胶原蛋白积累，如在发生自发性促结缔组织增生性乳腺肿瘤的MMTV-PyMT小鼠中。在所有模型中，与野生型对照相比，ADAMTS2基因敲除小鼠的原发性肿瘤生长显著增加，证实ADAMTS2具有抗肿瘤特性。形成鲜明对比的是，ADAMTS2基因敲除小鼠几乎阻止了乳腺肿瘤肺转移的扩散，显示出ADAMTS2在癌症进展的不同阶段具有有益或有害的双重作用。进一步的研究，特别是通过流式细胞术和单细胞测序，表明ADAMTS2对原发性肿瘤的作用不是直接作用于癌细胞，而是源于肿瘤内先天免疫系统的改变，在没有ADAMTS2的情况下，这种免疫系统变得更具免疫抑制性。
我们已经表明，ADAMTS2通过抑制免疫抑制微环境的逐步形成来抑制肿瘤生长。相反，它的存在有利于肺转移的有效形成。这些数据确定ADAMTS2是一种具有拮抗功能的癌症调节因子，限制初始进展但促进有效的转移扩散。
