Spon2, also referred to as M-spondin or DIL-1, is a member of the Mindin-F-spondin (FS) extracellular matrix protein family. It has diverse biological functions, such as promoting growth, development, and cell proliferation in normal tissues. It is involved in various signaling pathways, like the integrin β1/PYK2 axis, NF-κB, and Notch signaling pathways, and is of great biological importance, especially in the context of tumor-related processes [1].

In a mouse model of systemic sclerosis, Spon2 (Mindin) produced by SNAI1 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, revealing its role in promoting metastasis through activation of the NF-κB signaling pathway [3]. In triple-negative breast cancer, knockdown of Spon2 inhibited cell proliferation, migration, invasion, and tumorigenic ability while promoting apoptosis in nude mice, suggesting its potential as a therapeutic target [4]. In NK cell-specific Spon2-knockout mice, it was shown that Spon2 enhances IFNγ secretion and NK cell infiltration at the invasive front, with implications for predicting hepatocellular carcinoma recurrence [5]. In gastric cancer xenograft mice, SPON2 silencing decreased tumor growth, indicating its role in promoting tumor progression [6]. In hepatocellular carcinoma, different integrin-related signaling pathways mediated by SPON2 in M1-like macrophages and cancer cells were revealed through in vivo models, showing its dual functions in the tumor microenvironment [7]. In lung adenocarcinoma, tumor-derived exosomal HOTAIRM1 was found to regulate SPON2 in cancer-associated fibroblasts to promote cancer progression [8]. In colorectal cancer, SPON2 overexpression in intrasplenically transplanted NOD/SCID mice induced liver metastasis, and high SPON2 expression in patients was associated with shorter metastasis-free survival [9].

In conclusion, Spon2 plays crucial roles in various biological processes, especially in tumor-related functions such as metastasis, growth, and immune cell infiltration. Gene-knockout mouse models, like NK cell-specific Spon2-knockout mice, have been instrumental in revealing these functions in diseases like systemic sclerosis, multiple types of cancer, and potentially in predicting cancer recurrence. The study of Spon2 provides valuable insights into disease mechanisms and potential therapeutic targets.