TSPAN12 is a critical factor for cancer–fibroblast cell contact-mediated cancer invasion

Abstract

Communication between cancer cells and their microenvironment controls cancer progression. Although the tumor suppressor p53 functions in a cell-autonomous manner, it has also recently been shown to function in a non-cell-autonomous fashion. Although functional defects have been reported in p53 in stromal cells surrounding cancer, including mutations in the p53 gene and decreased p53 expression, the role of p53 in stromal cells during cancer progression remains unclear. We herein show that the expression of α-smooth muscle actin (α-SMA), a marker of cancerassociated fibroblasts (CAFs), was increased by the ablation of p53 in lung fibroblasts. CAFs enhanced the invasion and proliferation of lung cancer cells when cocultured with p53-depleted fibroblasts and required contact between cancer and stromal cells. A comprehensive analysis using a DNA chip revealed that tetraspanin 12 (TSPAN12), which belongs to the tetraspanin protein family, was derepressed by p53 knockdown. TSPAN12 knockdown in p53-depleted fibroblasts inhibited cancer cell proliferation and invasion elicited by coculturing with p53-depleted fibroblasts in vitro, and inhibited tumor growth in vivo. It also decreased CXC chemokine ligand 6 (CXCL6) secretion through the β-catenin signaling pathway, suggesting that cancer cell contact with TSPAN12 in fibroblasts transduced β-catenin signaling into fibroblasts, leading to the secretion of CXCL6 to efficiently promote invasion. These results suggest that stroma-derived p53 plays a pivotal role in epithelial cancer progression and that TSPAN12 and CXCL6 are potential targets for lung cancer therapy.cancer-associated fibroblasts | cancer invasion | cancer-stromal cell interaction | p53 | tetraspanin family

Gene aberrations for precision medicine against lung adenocarcinoma

“…Consistent with this, several studies reported that loss of TP53 function promotes the development of an invasive ⁄ metastatic tumor phenotype. (53,54) These observations suggest that targeting cells with aberrant TP53 function, for example, by attacking vulnerabilities cause by TP53 dysfunction (55,56) or restoring the function of abnormal TP53 protein, (57) might be an effective strategy against tumors harboring such mutations.…”

TSPAN12 Is a Norrin Co-receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling

“…TSPAN12, for example, is implicated in cancer (Knoblich et al, 2014; Otomo et al, 2014). Despite the interest in this protein family, the molecular basis of tetraspanin activity remains incompletely understood (Charrin et al, 2014).…”

Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment

“…Luga et al revealed that CAFs-secreted exosomes promote breast cancer cell protrusive activity, motility, and metastasis via Wnt-planar cell polarity signaling[30].Some studies have demonstrated direct interactions between CAFs and cancer cells for proliferation, migration, cancer survival, and metastasis. In basal-like breast cancer and non-small cell lung cancer (NSCLC), CAFs promote proliferation, migration, and invasion of cancer cells under direct cell-to-cell contact[31][32]. Otomo et al reported that tetraspanin 12, a transmembrane protein, in CAFs facilitate NSCLC cell invasion through direct cell contact[32].…”

“…In basal-like breast cancer and non-small cell lung cancer (NSCLC), CAFs promote proliferation, migration, and invasion of cancer cells under direct cell-to-cell contact[31][32]. Otomo et al reported that tetraspanin 12, a transmembrane protein, in CAFs facilitate NSCLC cell invasion through direct cell contact[32].…”