金德勒综合征 (KS) 是一种罕见的遗传性皮肤病，由编码 Kindlin-1 的基因 FERMT1 功能缺失突变引起。 KS 患者极有可能发展为侵袭性和转移性皮肤鳞状细胞癌 (cSCC)。在这里，我们在非 KS 相关患者中发现，与正常皮肤相比，光化性角化病中 FERMT1 表达升高，而 cSCC 中的进一步增加支持了该人群中的促肿瘤作用。相比之下，我们发现 Kindlin-1 的缺失会导致体内和 3D 球体中 SCC 肿瘤生长的增加，这与缺氧肿瘤环境的发展和糖酵解的增加有关。金属蛋白酶 Mmp13 在 Kindlin-1 耗尽的肿瘤中上调，并且 MMP13 表达的增加导致了 Kindlin-1 耗尽的 SCC 细胞的侵袭增加。这些结果提供了证据，表明 SCC 中的 Kindlin-1 缺失可以通过 MMP13 的上调促进侵袭，并为 Kindlin-1 缺失如何导致有利于肿瘤生长的缺氧环境的发展提供了新的见解。© 2024。作者（s）。

Kindler syndrome (KS) is a rare genodermatosis resulting from loss-of-function mutations in FERMT1, the gene that encodes Kindlin-1. KS patients have a high propensity to develop aggressive and metastatic cutaneous squamous cell carcinoma (cSCC). Here we show in non-KS-associated patients that elevation of FERMT1 expression is increased in actinic keratoses compared to normal skin, with a further increase in cSCC supporting a pro-tumorigenic role in this population. In contrast, we show that loss of Kindlin-1 leads to increased SCC tumor growth in vivo and in 3D spheroids, which was associated with the development of a hypoxic tumor environment and increased glycolysis. The metalloproteinase Mmp13 was upregulated in Kindlin-1-depleted tumors, and increased expression of MMP13 was responsible for driving increased invasion of the Kindlin-1-depleted SCC cells. These results provide evidence that Kindlin-1 loss in SCC can promote invasion through the upregulation of MMP13, and offer novel insights into how Kindlin-1 loss leads to the development of a hypoxic environment that is permissive for tumor growth.© 2024. The Author(s).