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A mechanistic basis for the malignant progression of salivary gland tumors.

ABSTRACT: Salivary gland tumors are diverse neoplasms, likely reflecting differences in the tissue- and cell-of-origin. 80%-90% of tumors arising in the sublingual gland (SLG) are malignant, whereas the other major glands often form benign tumors. Owing to the lack of experimental models to explore the etiology of salivary gland tumors, the cellular and molecular bases of malignancy remain unknown. Here, we generated a murine model of HRAS^G12V-driven salivary gland tumors amenable to examine tumor onset and malignant progression. We found that HMGA2 marks the tumor onset, and transformed-SOX2⁺ stem/progenitor cells expand exclusively in SLG tumors. Lineage tracing experiments showed that SLG tumor cells undergo an extensive epithelial-mesenchymal transition (EMT) and TGF-β-responding tumor cells are a source of mesenchymal tumor cells invading the surrounding stroma. This study advances our understanding of the mechanistic basis of salivary gland malignancy and may help combat this highly heterogeneous cancer.

SUBMITTER: Taniguchi S

PROVIDER: S-EPMC8661530 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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A mechanistic basis for the malignant progression of salivary gland tumors.

Taniguchi Sachiko S Tanaka Yuya Y Elhance Ajit A Oshimori Naoki N

iScience 20211125 12

Salivary gland tumors are diverse neoplasms, likely reflecting differences in the tissue- and cell-of-origin. 80%-90% of tumors arising in the sublingual gland (SLG) are malignant, whereas the other major glands often form benign tumors. Owing to the lack of experimental models to explore the etiology of salivary gland tumors, the cellular and molecular bases of malignancy remain unknown. Here, we generated a murine model of HRAS<sup>G12V</sup>-driven salivary gland tumors amenable to examine tu ...[more]

PMID: 34934927

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Project description:Rationale: Immunosuppression in the tumor microenvironment (TME) is key to the pathogenesis of solid tumors. Tumor cell-intrinsic autophagy is critical for sustaining both tumor cell metabolism and survival. However, the role of autophagy in the host immune system that allows cancer cells to escape immune destruction remains poorly understood. Here, we determined if attenuated host autophagy is sufficient to induce tumor rejection through reinforced adaptive immunity. Furthermore, we determined whether dietary glutamine supplementation, mimicking attenuated host autophagy, is capable of promoting antitumor immunity. Methods: A syngeneic orthotopic tumor model in Atg5+/+ and Atg5flox/flox mice was established to determine the impact of host autophagy on the antitumor effects against mouse malignant salivary gland tumors (MSTs). Multiple cohorts of immunocompetent mice were used for oncoimmunology studies, including inflammatory cytokine levels, macrophage, CD4+, and CD8+ cells tumor infiltration at 14 days and 28 days after MST inoculation. In vitro differentiation and in vivo dietary glutamine supplementation were used to assess the effects of glutamine on Treg differentiation and tumor expansion. Results: We showed that mice deficient in the essential autophagy gene, Atg5, rejected orthotopic allografts of isogenic MST cells. An enhanced antitumor immune response evidenced by reduction of both M1 and M2 macrophages, increased infiltration of CD8+ T cells, elevated IFN-γ production, as well as decreased inhibitory Tregs within TME and spleens of tumor-bearing Atg5flox/flox mice. Mechanistically, ATG5 deficiency increased glutamine level in tumors. We further demonstrated that dietary glutamine supplementation partially increased glutamine levels and restored potent antitumor responses in Atg5+/+ mice. Conclusions: Dietary glutamine supplementation exposes a previously undefined difference in plasticity between cancer cells, cytotoxic CD8+ T cells and Tregs.

Project description:Purpose The clinical practice of elastosonography for the detection of salivary gland tumors is still a controversial issue. The objective of this meta-analysis was to evaluate the effect of elastosonography for the diagnosis of salivary gland tumors and to compare the diagnostic value of elastosonography and conventional ultrasound in the diagnosis of salivary gland tumors. Methods A comprehensive literature search through PubMed, EMBASE, and Cochrane Library was carried out from inception to November 2021. Two researchers independently extracted the data from the enrolled papers using a standard data extraction form. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were calculated to evaluate the diagnostic performance of elastosonography. The Quality Assessment of Diagnostic Accuracy Studies—2 (QUADAS-2) tool was utilized to evaluate the quality of each included study. Meta-DiSc version 1.4, Review Manager 5.3, and StataSE 15 were used. Results Sixteen studies with a total of 1105 patients with 1146 lesions were included in this meta-analysis. The pooled sensitivity, specificity, PLR, NLR, and DOR of elastosonography for the differentiation between benign and malignant salivary gland tumors were 0.73 (95%CI, 0.66–0.78), 0.64 (95%CI, 0.61–0.67), 2.83 (95%CI, 1.97–4.07), 0.45 (95%CI, 0.32–0.62), and 9.86 (95%CI, 4.49–21.62), respectively, with an AUC of 0.82. Four studies provided data regarding the conventional ultrasound for the differentiation between benign and malignant salivary gland tumors. The pooled sensitivity, specificity, and DOR were 0.62 (95%CI, 0.50–0.73), 0.93 (95%CI, 0.90–0.96), and 25.07 (95%CI, 4.28–146.65), respectively. The meta-regression and subgroup analyses found that assessment methods were associated with significant heterogeneity, and quantitative or semiquantitative elastosonography performed better than the qualitative one. Conclusions Elastosonography showed a limited value for diagnosing malignant salivary gland tumors; it could be considered as a supplementary diagnostic technology to conventional ultrasound, and quantitative or semiquantitative elastosonography was superior to the qualitative one.

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A mechanistic basis for the malignant progression of salivary gland tumors.

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A mechanistic basis for the malignant progression of salivary gland tumors.

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