Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo

Conroy, Lindsey R.; Dougherty, Susan; Kruer, Traci; Metcalf, Stephanie; Lorkiewicz, Pawel; He, Liqing; Yin, Xinmin; Zhang, Xiang; Arumugam, Sengodagounder; Young, Lyndsay E.A.; Sun, Ramon C.; Clem, Brian F.

doi:10.3390/cancers12010237

Cited by 14 publications

(14 citation statements)

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“…Moreover, we observed significant differences in genomic alteration patterns between the 4 metabolic subgroups. RB1 is a well-known tumor suppressor gene, and its deletion can enhance glycolytic metabolism and driving tumor progression [ 43 ]. A recent study also identified LRP1B, which encodes low-density lipoprotein receptor-related protein 1B, as a novel tumor suppressor, and LRP1B deletion was associated with chemotherapy resistance in ovarian cancer [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Alteration in glycolytic/cholesterogenic gene expression is associated with bladder cancer prognosis and immune cell infiltration

et al. 2022

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Background Oncogenic metabolic reprogramming contributes to tumor growth and immune evasion. The intertumoral metabolic heterogeneity and interaction of distinct metabolic pathways may determine patient outcomes. In this study, we aim to determine the clinical and immunological significance of metabolic subtypes according to the expression levels of genes related to glycolysis and cholesterol-synthesis in bladder cancer (BCa). Methods Based on the median expression levels of glycolytic and cholesterogenic genes, patients were stratified into 4 subtypes (mixed, cholesterogenic, glycolytic, and quiescent) in an integrated cohort including TCGA, GSE13507, and IMvigor210. Clinical, genomic, transcriptomic, and tumor microenvironment characteristics were compared between the 4 subtypes. Results The 4 metabolic subtypes exhibited distinct clinical, molecular, and genomic patterns. Compared to quiescent subtype, mixed subtype was more likely to be basal tumors and was significantly associated with poorer prognosis even after controlling for age, gender, histological grade, clinical stage, and molecular phenotypes. Additionally, mixed tumors harbored a higher frequency of RB1 and LRP1B copy number deletion compared to quiescent tumors (25.7% vs. 12.7 and 27.9% vs. 10.2%, respectively, both adjusted P value< 0.05). Furthermore, aberrant PIK3CA expression level was significantly correlated with those of glycolytic and cholesterogenic genes. The quiescent subtype was associated with lower stemness indices and lower signature scores for gene sets involved in genomic instability, including DNA replication, DNA damage repair, mismatch repair, and homologous recombination genes. Moreover, quiescent tumors exhibited lower expression levels of pyruvate dehydrogenase kinases 1-3 (PDK1-3) than the other subtypes. In addition, distinct immune cell infiltration patterns were observed across the 4 metabolic subtypes, with greater infiltration of M0/M2 macrophages observed in glycolytic and mixed subtypes. However, no significant difference in immunotherapy response was observed across the 4 metabolic subtypes. Conclusion This study proposed a new metabolic subtyping method for BCa based on genes involved in glycolysis and cholesterol synthesis pathways. Our findings may provide novel insight for the development of personalized subtype-specific treatment strategies targeting metabolic vulnerabilities.

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Section: Discussionmentioning

confidence: 99%

Alteration in glycolytic/cholesterogenic gene expression is associated with bladder cancer prognosis and immune cell infiltration

et al. 2022

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“… 21 In the kras‐driven lung cancers, loss of RB1 promotes a glycolytic phenotype but does not alter pyruvate oxidative metabolism or glutamine inactivation. 22 It has been suggested that EGFR/TP53/RB1 mutant lung cancers have a unique risk of histological transformation, with 25% of lung cancers exhibiting ab initio small cell lung cancer or eventual small cell transformation. 23 Another meta‐analysis has shown that loss of RB1 function leads to a 1.6 two‐fold increase in the mortality of patients with osteosarcoma, a significant increase in osteosarcoma metastasis, and a notable decrease in osteosarcoma response to chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Analysis of risk factors and gene mutation characteristics of different metastatic sites of lung cancer

et al. 2021

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Risk factors vary in terms of the pattern of lung cancer metastasis and specific metastatic organs. In this study, we retrospectively analyzed the clinical risk factors of tumor metastasis in lung cancer patients and used second-generation gene sequencing to characterize relevant gene mutations. The risk factors of different metastatic sites of real-world lung cancer were explored to find the differentially expressed genes and risk factors in different metastatic organs, which laid a foundation for further study on the metastasis patterns and mechanisms of lung cancer. The clinical risk factors of tumor metastasis in 137 lung cancer patients who attended our department from May 2017 to March 2019 were retrospectively analyzed and grouped based on bone metastasis, brain metastasis, other distant metastasis, and no metastasis. Single-or multi-factor logistic regression analysis was performed to analyze the effect of neutrophil/lymphocyte ratio/platelet/lymphocyte ratio/lymphocyte to monocyte ratio on platelets (PLTs) and bone metastasis by combining PLT values, age, pathology type, gender, and smoking history.Based on the presence or absence of bone metastasis, distal metastasis, and PLT values of lung cancer, 39 tissue specimens of primary lung cancer were taken for 773 gene grouping and gene mutation characterization. The tumor mutation load, gene copy number instability, microsatellite instability, and tumor heterogeneity among different groups were analyzed. Age and PLT level were independent risk factors for bone metastasis and distal metastasis, but not for brain metastasis. The RB1 gene was mutated during bone metastasis, and tumor heterogeneity was less in the elevated PLT group. PLT values were an independent risk factor for distant metastases from lung cancer other than the brain. Age has a significant effect on bone metastasis formation. RB1 gene mutation was significantly associated with bone metastasis.

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“…Whether the regulation of CDK4 on cancer metabolism is predominantly exerted by its direct effect or via insulin secretion will require further elucidation. Meanwhile, the loss of Rb can also lead to a dependence on the metabolism of aerobic glycolysis 57‐60 …”

Section: Glucose Metabolism and Cell Cyclementioning

confidence: 99%

“…Meanwhile, the loss of Rb can also lead to a dependence on the metabolism of aerobic glycolysis. [57][58][59][60]…”

Section: Glucose Homeostasismentioning

confidence: 99%

Out of the cycle: Impact of cell cycle aberrations on cancer metabolism and metastasis

Cheung

Hui

Wong

et al. 2022

Intl Journal of Cancer

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The use of cell cycle inhibitors has necessitated a better understanding of the cell cycle in tumor biology to optimize the therapeutic approach. Cell cycle aberrations are common in cancers, and it is increasingly acknowledged that these aberrations exert oncogenic effects beyond the cell cycle. Multiple facets such as cancer metabolism, immunity and metastasis are also affected, all of which are beyond the effect of cell proliferation alone. This review comprehensively summarized the important recent findings and advances in these interrelated processes. In cancer metabolism, cell cycle regulators can modulate various pathways in aerobic glycolysis, glucose uptake and gluconeogenesis, mainly through transcriptional regulation and kinase activities. Amino acid metabolism is also regulated through cell cycle progression. On cancer metastasis, metabolic plasticity, immune evasion, tumor microenvironment adaptation and metastatic site colonization are intricately related to the cell cycle, with distinct regulatory mechanisms at each step of invasion and dissemination. Throughout the synthesis of current understanding, knowledge gaps and limitations in the literature are also highlighted, as are new therapeutic approaches such as combinational therapy and challenges in tackling emerging targeted therapy resistance. A greater understanding of how the cell cycle modulates diverse aspects of cancer biology can hopefully shed light on identifying new molecular targets by harnessing the vast potential of the cell cycle.

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Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo

Cited by 14 publications

References 50 publications

Alteration in glycolytic/cholesterogenic gene expression is associated with bladder cancer prognosis and immune cell infiltration

Alteration in glycolytic/cholesterogenic gene expression is associated with bladder cancer prognosis and immune cell infiltration

Analysis of risk factors and gene mutation characteristics of different metastatic sites of lung cancer

Out of the cycle: Impact of cell cycle aberrations on cancer metabolism and metastasis

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