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Inhibition of Alk signaling promotes the induction of human salivary gland-derived organoids.

ABSTRACT: Hyposalivation and xerostomia are the cause of several conditions of morbidities such as dental caries, painful mucositis, oral fungal infections, sialadenitis and dysphagia. For these reasons, preservation of normal saliva secretion is critical for the maintenance of functionally normal oral homeostasis and finally for keeping good health. Several strategies for restoring salivary gland hypofunction have been reported from different points of view based on such salivary gland-derived epithelial stem/progenitor cells and tissue engineering approaches to induce organoids mimicking in vivo salivary glands. In this study, we clarified that inhibition of Activin receptor-like kinase (Alk) signaling was essential for the induction of human salivary gland-derived organoids and showed their usefulness as an inflammatory disease model. In the inflammatory conditions like sialadenitis, in general, pro-inflammatory cytokines such as tumor necrosis factor-? (TNF-?) are upregulated but their function is still unclear. In our established human salivary gland-derived organoid culture system, we successfully induced an organoid swelling revealing the function of saliva secretion by the stimulation of carbachol, a non-selective cholinergic agonist, and forskolin, an activator of cystic fibrosis transmembrane conductance regulator (CFTR). Furthermore, we found that this organoid swelling was inhibited by TNF-?. From these results, we could clarify the inhibitory function of TNF-? on the saliva secretion in vitro Thus, our established human salivary gland-derived organoids would be able to be useful for the in vitro analyses of the morphological and functional changes of salivary gland dysfunctions in several research fields such as pathobiology, inflammation and regenerative medicine.

SUBMITTER: Yoshimoto S

PROVIDER: S-EPMC7541338 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Inhibition of Alk signaling promotes the induction of human salivary-gland-derived organoids.

Yoshimoto Shohei S Yoshizumi Junko J Anzai Hiromasa H Morishita Koichiro K Okamura Kazuhiko K Hiraki Akimitsu A Hashimoto Shuichi S

Disease models & mechanisms 20200928 9

Hyposalivation and xerostomia are the cause of several morbidities, such as dental caries, painful mucositis, oral fungal infections, sialadenitis and dysphagia. For these reasons, preservation of normal saliva secretion is critical for the maintenance of functionally normal oral homeostasis and for keeping good health. Several strategies for restoring salivary gland function have been reported, from different points of view, based on the use of salivary-gland-derived epithelial stem/progenitor ...[more]

PMID: 32801121

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Project description:Patients with advanced salivary gland mucoepidermoid carcinoma (MEC) are treated with surgery and radiotherapy, as current systemic therapies are largely ineffective. As such, current treatment frequently leads to poor long-term survival due to locoregional recurrence or metastases. We have shown that salivary gland cancer stem cells (CSCs) are resistant to platinum-based chemotherapy and drive tumor progression. The purpose of this study was to investigate the effect of therapeutic inhibition of mTOR (mechanistic target of rapamycin) on resistance of CSCs to cisplatin, a prototypic platinum-based chemotherapeutic agent. Viability assays determined the effect of several inhibitors of PI3k/mTOR signaling (e.g., temsirolimus, BKM120, AZD8055, PF4708671) and/or cisplatin on survival of human MEC cells. The impact of mTOR inhibitors and/or cisplatin on MEC stemness was examined with salisphere assays, flow cytometry for ALDH/CD44 (CSC markers for MEC), and Western blots for Bmi-1 expression (marker of stem cell self-renewal). Salivary gland MEC patient-derived xenografts were used to examine the effect of cisplatin and/or temsirolimus on CSCs in vivo. We observed that cisplatin induced mTOR and S6K1 phosphorylation, increased the number and size of MEC salispheres, and induced Bmi-1 expression and the fraction of CSCs in MEC models in vitro. Cisplatin also increased the fraction of CSCs in vivo. In contrast, mTOR inhibition (e.g., temsirolimus) blocked cisplatin-induced Bmi-1 expression and salisphere formation in vitro. Remarkably, temsirolimus slowed down tumor growth and decreased the fraction of CSCs (P < 0.05) even in presence of cisplatin in a short-term in vivo experiment. Collectively, these results demonstrate that therapeutic inhibition of mTOR ablates cytotoxic-resistant CSCs, and they suggest that a combination of an mTOR inhibitor and platinum-based chemotherapy might be beneficial to patients with salivary gland mucoepidermoid carcinoma.

Dataset Information

Inhibition of Alk signaling promotes the induction of human salivary gland-derived organoids.

Publications

Inhibition of Alk signaling promotes the induction of human salivary-gland-derived organoids.

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