Spon2, also referred to as M-spondin or DIL-1, is a member of the Mindin-F-spondin extracellular matrix protein family. It has diverse biological functions such as promoting growth, development, and cell proliferation in normal tissues. In disease contexts, it is involved in multiple signaling pathways, including integrin-related pathways, NF-κB, and Notch signaling, and is associated with various diseases, especially cancer [1].

In a mouse model of systemic sclerosis, Spon2 (Mindin) produced by transgenic skin keratinocytes was found to be essential for cutaneous fibrogenesis by inducing early inflammatory cytokine production and collagen secretion in dermal fibroblasts [2].

In lung adenocarcinoma, silencing Spon2 in vivo significantly reduced bone metastasis, as Spon2 activates the NF-κB signaling pathway to promote metastasis [3].

In triple-negative breast cancer, knockdown of Spon2 inhibited cell proliferation, migration, invasion, and tumorigenic ability in nude mice and promoted apoptosis [4].

In gastric cancer, Spon2 silencing decreased cell proliferation and motility and reduced tumor growth in xenograft mice, while overexpression had the opposite effects [6].

In hepatocellular carcinoma, studies using NK cell-specific Spon2-knockout mice revealed that Spon2 enhances IFNγ secretion and NK cell infiltration at the invasive front [5]. Also, in HCC, SPON2 promotes M1-like macrophage recruitment and inhibits tumor metastasis through distinct integrin-Rho GTPase-Hippo pathways [7].

In conclusion, Spon2 plays crucial roles in multiple biological processes and disease conditions, especially in cancer progression and metastasis. Gene knockout and conditional knockout mouse models have significantly contributed to understanding its functions in diseases like systemic sclerosis, various cancers including lung adenocarcinoma, triple-negative breast cancer, gastric cancer, and hepatocellular carcinoma, providing insights for potential therapeutic targets.