Survival of salivary gland cancer stem cells requires mTOR signaling

Abstract

Advanced salivary gland mucoepidermoid carcinoma (MEC) is a relentless cancer that exhibits resistance to conventional chemotherapy. As such, treatment for patients with advanced MEC is tipically radical surgery and radiotherapy. Facial disfigurement and poor quality of life are frequent treatment challenges, and many patients succumb to loco-regional recurrence and/or metastasis. We know that cancer stem-like cells (CSC) drive MEC tumorigenesis. The current study tests the hypothesis that MEC CSC are sensitive to therapeutic inhibition of mTOR. Here, we report a correlation between the long-term clinical outcomes of 17 MEC patients and the intratumoral expression of p-mTOR (p = 0.00294) and p-S6K1 (p = 0.00357). In vitro, we observed that MEC CSC exhibit constitutive activation of the mTOR signaling pathway (i.e., mTOR, AKT, and S6K1), unveiling a potential strategy for targeted ablation of these cells. Using a panel of inhibitors of the mTOR pathway, i.e., rapamycin and temsirolimus (mTOR inhibitors), buparlisib and LY294002 (AKT inhibitors), and PF4708671 (S6K1 inhibitor), we observed consistently dose-dependent decrease in the fraction of CSC, as well as inhibition of secondary sphere formation and self-renewal in three human MEC cell lines (UM-HMC-1,-3A,-3B). Notably, therapeutic inhibition of mTOR with rapamycin or temsirolimus induced preferential apoptosis of CSC, when compared to bulk tumor cells. In contrast, conventional chemotherapeutic drugs (cisplatin, paclitaxel) induced preferential apoptosis of bulk tumor cells and accumulation of CSC. In vivo, therapeutic inhibition of mTOR with temsirolimus caused ablation of CSC and downregulation of Bmi-1 expression (major inducer of stem cell self-renewal) in MEC xenografts. Transplantation of MEC cells genetically silenced for mTOR into immunodeficient mice corroborated the results obtained with temsirolimus. Collectively, these data demonstrated that mTOR signaling is required for CSC survival, and unveiled the therapeutic potential of targeting the mTOR pathway for elimination of highly tumorigenic cancer stem-like cells in salivary gland mucoepidermoid carcinoma.

Epithelial–mesenchymal transition and cancer stem cells: A route to acquired cisplatin resistance through epigenetics in HNSCC

“…Cancer stem cells populations are correlated with tumor aggressiveness and resistance to therapy, causing recurrences in numerous cancers. In fact, cisplatin administration enriches CSC population in adenoid cystic carcinoma (Almeida et al, 2017) mucoepidermoid carcinoma (Andrade et al, 2021) and in HNSCC (Nör et al, 2014), which is in agreement with our findings; when the cells were exposed to cisplatin, there was a progressive accumulation of the CSC subpopulation in cell lines with increasing levels of cisplatin resistance.…”

A Synopsis of Signaling Crosstalk of Pericytes and Endothelial Cells in Salivary Gland

“…AKT manages cell growth by entailing the phosphorylation of mTOR [ 67 ]. Markedly, The PI3K/AKT signaling pathway is upregulated in SGTs and hyperactivates, in part, mTOR, as a chief regulator of manifold cellular events such as cancer cell survival and metastasis [ 81 , 82 , 83 ]. PI3K signaling is usually intensified by the loss of function of the negative regulation of PTEN, whose main substrate is PIP3, thus enhancing the activation of AKT [ 84 , 85 ].…”

“…Basically, TME is characterized by heterogeneous, aberrant vasculature derived from an imbalance among pro- and non-angiogenic factors [ 88 , 89 ]. Intriguingly, mTOR composes networks of crosstalk with the signaling pathways within the PI3K/AKT pathway [ 90 ] and the inhibition of mTOR determines the minimization of MVD and suppresses the tumor growth [ 82 ]. In addition to the chemotherapeutic drugs, such as bevacizumab and temozolomide, which inhibit VEGF in a paracrine loop and [ 10 , 91 , 92 , 93 ] provide the rationale to inhibit tumor progression, sorafenib, a multi-Tyrosine Kinase Inhibitor (mTKI), has been shown to restrict the action of VEGFR2, RAS kinase, and PDGFR, [ 94 ] targeting twofold PCs and ECs through the hindrance of the autocrine VEGF signaling loop [ 10 ].…”

mTOR pathway as a potential therapeutic target for cancer stem cells in canine mammary carcinoma

“…In human breast cancer, mTOR activation in CSCs is important for colony-forming and tumorigenicity ( 39 ). Activation of mTOR in CSCs has been reported in various cancers, such as colon cancer, prostate cancer, salivary gland cancer, and glioblastoma ( 40 – 43 ). mTOR signaling suppression reduces aldehyde dehydrogenase activity, which is abundant in immature cells, such as stem cells, in colon cancer ( 44 ).…”