Biology subjects

Noji, M. C.

Publications and source records attributed to Noji, M. C..

3 recordsLinked to original sources

bioRxiv2025

Opposing effects of systemic and pancreas-specific inhibition of BCKDK on pancreatic carcinogenesis

Branched-chain amino acid (BCAA) metabolism is perturbed in patients with pancreatic cancer, but the contribution of systemic or pancreas-intrinsic BCAA catabolism to pancreatic carcinogenesis is unclear. We show here that pancreas-specific loss of DBT, the E2 subunit of the branched-chain keto-acid dehydrogenase (BCKDH) complex required for BCAA oxidation, strikingly exacerbates premalignant pancreatic intraepithelial neoplasia (PanIN) lesions in KC (p48-Cre;KrasLSL-G12D/+) mice. However, deletion of upstream enzyme BCAT2 neither phenocopied nor rescued loss of DBT in KC mice, ruling out involvement of both upstream and downstream metabolites as mediators of PanIN promotion. Instead, we observed that DBT deficiency led to loss of the kinase BCKDK, a negative regulator of the BCKDH complex, and that, remarkably, pancreas-specific loss of BCKDK phenocopied DBT deficiency in accelerating PanIN formation. These data thus support a model in which pancreas BCKDK restrains tumorigenesis. In contrast, systemic treatment of KC mice with the BCKDK inhibitor BT2, which inhibits BCKDH phosphorylation across many tissues except the pancreas, reduced PanIN formation and preserved normal acinar area. Together the data reveal the promotion of BCAA catabolism systemically, but not within the pancreas, as a promising intervention strategy to suppress tumor initiation.

cancer biology↗

bioRxiv2024

Glutamine availability regulates cDC subsets in tissue

AbstractProliferating tumor cells take up glutamine for anabolic processes engendering glutamine deficiency in the tumor microenvironment. How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDC) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets - cDC1 and cDC2, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on Glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mTOR signaling pathway in this process. Taken together, these findings uncover glutamine dependence of cDC1s that is coopted by tumors to escape immune responses. One Sentence SummaryType 1 conventional dendritic cells require glutamine to maintain their number in non-lymphoid tissue. SignificanceImmune evasion is a key hallmark of cancer; however, the underlying pathways are diverse, tumor-specific and not fully elucidated. Many tumor cells avidly import glutamine to support their anabolic needs, creating a glutamine-deficient tumor microenvironment (TME). Herein, using mouse models of soft tissue sarcomas, we show that glutamine depletion in TME leads to reduced type 1 conventional dendritic cells - a cell type that is critical for adaptive immune responses. This work is a paradigm for how tumor cell metabolism can regulate anti-tumor immune responses and will be foundational to future efforts targeting glutamine metabolism for cancer immunotherapy.

immunology↗

bioRxiv2023

The mitochondrial Ca2+ channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation

The mitochondrial uniporter (MCU) Ca2+ ion channel represents the primary means for Ca2+ uptake into mitochondria. Here we employed in vitro and in vivo models with MCU genetically eliminated to understand how MCU contributes to tumor formation and progression. Transformation of primary fibroblasts in vitro was associated with increased MCU expression, enhanced mitochondrial Ca2+ uptake, suppression of inactivating-phosphorylation of pyruvate dehydrogenase, a modest increase of basal mitochondrial respiration and a significant increase of acute Ca2+-dependent stimulation of mitochondrial respiration. Inhibition of mitochondrial Ca2+ uptake by genetic deletion of MCU markedly inhibited growth of HEK293T cells and of transformed fibroblasts in mouse xenograft models. Reduced tumor growth was primarily a result of substantially reduced proliferation and fewer mitotic cells in vivo, and slower cell proliferation in vitro associated with delayed progression through S-phase of the cell cycle. MCU deletion inhibited cancer stem cell-like spheroid formation and cell invasion in vitro, both predictors of metastatic potential. Surprisingly, mitochondrial matrix Ca2+ concentration, membrane potential, global dehydrogenase activity, respiration and ROS production were unchanged by genetic deletion of MCU in transformed cells. In contrast, MCU deletion elevated glycolysis and glutaminolysis, strongly sensitized cell proliferation to glucose and glutamine limitation, and altered agonist-induced cytoplasmic Ca2+ signals. Our results reveal a dependence of tumorigenesis on MCU, mediated by a reliance on mitochondrial Ca2+ uptake for cell metabolism and Ca2+ dynamics necessary for cell-cycle progression and cell proliferation.

cancer biology↗