Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.
Aix Marseille Univ, CNRS, I2M, Marseille, France.
Front Immunol. 2022 Feb 2;13:797244. doi: 10.3389/fimmu.2022.797244. eCollection 2022.
PTEN (Phosphatase and TENsin homolog) is a well-known tumor suppressor involved in numerous types of cancer, including T-cell acute lymphoblastic leukemia (T-ALL). In human, loss-of-function mutations of are correlated to mature T-ALL expressing a T-cell receptor (TCR) at their cell surface. In accordance with human T-ALL, inactivation of gene in mouse thymocytes induces TCRαβ T-ALL development. Herein, we explored the functional interaction between TCRαβ signaling and PTEN. First, we performed single-cell RNA sequencing (scRNAseq) of PTEN-deficient and PTEN-proficient thymocytes. Bioinformatic analysis of our scRNAseq data showed that pathological Pten thymocytes express, as expected, transcript, whereas inference of pathway activity revealed that these Pten thymocytes display a lower calcium pathway activity score compared to their physiological counterparts. We confirmed this result using calcium flux assay and showed that upon TCR activation tumor Pten blasts were unable to release calcium ions (Ca) from the endoplasmic reticulum to the cytosol. In order to understand such phenomena, we constructed a mathematical model centered on the mechanisms controlling the calcium flux, integrating TCR signal strength and PTEN interactions. This qualitative model displays a dynamical behavior coherent with the dynamics reported in the literature, it also predicts that PTEN affects positively IP3 (inositol 1,4,5-trisphosphate) receptors (ITPR). Hence, we analyzed expression and unraveled that ITPR proteins levels are reduced in PTEN-deficient tumor cells compared to physiological and leukemic PTEN-proficient cells. However, calcium flux and ITPR proteins expression are not defective in non-leukemic PTEN-deficient T cells indicating that beyond PTEN loss an additional alteration is required. Altogether, our study shows that ITPR/Calcium flux is a part of the oncogenic landscape shaped by PTEN loss and pinpoints a putative role of PTEN in the regulation of ITPR proteins in thymocytes, which remains to be characterized.
PTEN（磷酸酶和张力蛋白同源物）是一种众所周知的肿瘤抑制因子，涉及多种癌症，包括 T 细胞急性淋巴细胞白血病（T-ALL）。在人类中， 的功能丧失突变与成熟 T-ALL 相关，这些 T-ALL 在其细胞表面表达 T 细胞受体（TCR）。与人类 T-ALL 一致，在小鼠胸腺细胞中失活 基因会诱导 TCRαβ T-ALL 的发展。在此，我们探讨了 TCRαβ 信号与 PTEN 之间的功能相互作用。首先，我们对 PTEN 缺失和 PTEN 功能正常的胸腺细胞进行了单细胞 RNA 测序（scRNAseq）。我们 scRNAseq 数据的生物信息学分析表明，病理性 Pten 胸腺细胞如预期的那样表达 转录本，而途径活性推断表明，与生理对照相比，这些 Pten 胸腺细胞的钙途径活性评分较低。我们使用钙通量测定法证实了这一结果，并表明在 TCR 激活时，肿瘤 Pten blasts 无法将内质网中的钙离子（Ca）释放到细胞质中。为了理解这种现象，我们构建了一个以控制钙通量的机制为中心的数学模型，整合了 TCR 信号强度和 PTEN 相互作用。该定性模型显示出与文献中报道的动力学一致的动态行为，它还预测 PTEN 正向影响 IP3（肌醇 1,4,5-三磷酸）受体（ITPR）。因此，我们分析了 表达，并揭示了与生理和白血病 PTEN 阳性细胞相比，PTEN 缺陷肿瘤细胞中的 ITPR 蛋白水平降低。然而，钙通量和 ITPR 蛋白表达在非白血病性 PTEN 缺失 T 细胞中没有缺陷，表明除了 PTEN 缺失外，还需要其他改变。总之，我们的研究表明，ITPR/钙通量是由 PTEN 缺失形成的致癌景观的一部分，并指出了 PTEN 在调节胸腺细胞中 ITPR 蛋白方面的潜在作用，这有待进一步研究。
