3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib.

Osimertinib sensitive and resistant NSCLC NCI-H1975 clones are used to model osimertinib acquired resistance in humanized and non-humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation are found in resistant clones. Resistant tumors grown under continuous osimertinib pressure both in humanized and non-humanized mice show aggressive tumor regrowth which is significantly less sensitive to osimertinib as compared with parental tumors. 3-phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitizes resistant clones. In-vivo inhibition of PDK1 enhances the osimertinib sensitivity against osimertinib resistant xenograft and a patient derived xenograft (PDX) tumors. PDK1 knock-out dysregulates PI3K/Akt/mTOR signaling, promotes cell cycle arrest at the G1 phase. Yes-associated protein (YAP) and active-YAP are upregulated in resistant tumors, and PDK1 knock-out inhibits nuclear translocation of YAP. Higher expression of PDK1 and an association between PDK1 and YAP are found in patients with progressive disease following osimertinib treatment. PDK1 is a central upstream regulator of two critical drug resistance pathways: PI3K/AKT/mTOR and YAP.

A Case Study of Chimeric Antigen Receptor T Cell Function: Donor Therapeutic Differences in Activity and Modulation with Verteporfin.

BACKGROUND: Chimeric antigen receptor (CAR) T cells have recently been demonstrated to extract and express cognate tumor antigens through trogocytosis. This process may contribute to tumor antigen escape, T cell exhaustion, and fratricide, which plays a central role in CAR dysfunction. We sought to evaluate the importance of this effect in epidermal growth factor receptor variant III (EGFRvIII) specific CAR T cells targeting glioma. METHODS: EGFRvIII-specific CAR T cells were generated from various donors and analyzed for cytotoxicity, trogocytosis, and in vivo therapeutic activity against intracranial glioma. Tumor autophagy resulting from CAR T cell activity was evaluated in combination with an autophagy inducer (verteporfin) or inhibitor (bafilomycin A1). RESULTS: CAR T cell products derived from different donors induced markedly divergent levels of trogocytosis of tumor antigen as well as PD-L1 upon engaging target tumor cells correlating with variability in efficacy in mice. Pharmacological facilitation of CAR induced-autophagy with verteporfin inhibits trogocytic expression of tumor antigen on CARs and increases CAR persistence and efficacy in mice. CONCLUSION: These data propose CAR-induced autophagy as a mechanism counteracting CAR-induced trogocytosis and provide a new strategy to innovate high-performance CARs through pharmacological facilitation of T cell-induced tumor death.

Neighborhood disadvantage and biological aging biomarkers among breast cancer patients.

Living in a disadvantaged neighborhood is associated with adverse clinical outcomes among breast cancer patients, but the underlying pathway is still unclear. Limited evidence has suggested that accelerated biological aging may play an important role. In this study, using a sub-sample of 906 women with newly diagnosed breast cancer at M.D. Anderson, we examined whether levels of selected markers of biological aging (e.g., allostatic load, telomere length, and global DNA methylation) were affected by neighborhood disadvantage. The Area Deprivation Index was used to determine the neighborhood disadvantage. Based on the median ADI at the national level, the study population was divided into low and high ADI groups. Overall, breast cancer patients from the high ADI group were more likely to be younger and non-Hispanic Black than those from the low ADI group (P < 0.001, respectively). They were also more likely to have higher grade and poorly differentiated breast tumors (P = 0.029 and 0.019, respectively). For the relationship with markers, compared to the low ADI group, high ADI group had higher median levels of allostatic load (P = 0.046) and lower median levels of global DNA methylation (P < 0.001). Compared to their counterparts, those from the high ADI group were 20% more likely to have increased allostatic load and 51% less likely to have increased levels of global DNA methylation. In summary, we observed that levels of allostatic load and global DNA methylation are influenced by neighborhood disadvantage among breast cancer patients.

Cell-directed aptamer therapeutic targeting for cancers including those within the central nervous system.

Osteopontin (OPN) is produced by tumor cells as well as by myeloid cells and is enriched in the tumor microenvironment (TME) of many cancers. Given the roles of OPN in tumor progression and immune suppression, we hypothesized that targeting OPN with aptamers that have high affinity and specificity could be a promising therapeutic strategy. Bi-specific aptamers targeting ligands for cellular internalization were conjugated to siRNAs to suppress OPN were created, and therapeutic leads were selected based on target engagement and in vivo activity. Aptamers as carriers for siRNA approaches were created including a cancer targeting nucleolin aptamer Ncl-OPN siRNA and a myeloid targeting CpG oligodeoxynucleotide (ODN)-OPN siRNA conjugate. These aptamers were selected as therapeutic leads based on 70-90% OPN inhibition in cancer (GL261, 344SQ, 4T1B2b) and myeloid (DC2.4) cells relative to scramble controls. In established immune competent 344SQ lung cancer and 4T1B2b breast cancer models, these aptamers, including in combination, demonstrate therapeutic activity by inhibiting tumor growth. The Ncl-OPN siRNA aptamer demonstrated efficacy in an immune competent orthotopic glioma model administered systemically secondary to the ability of the aptamer to access the glioma TME. Therapeutic activity was demonstrated using both aptamers in a breast cancer brain metastasis model. Targeted inhibition of OPN in tumor cells and myeloid cells using bifunctional aptamers that are internalized by specific cell types and suppress OPN expression once internalized may have clinical potential in cancer treatment.

Allostatic score and its associations with demographics, healthy behaviors, tumor characteristics, and mitochondrial DNA among breast cancer patients.

INTRODUCTION: Allostatic load (AL), a composite index, has been used to capture variation in life-course stresses. However, few studies have been carried out among breast cancer patients. METHODS: In this study, we examined the cross-sectional association of AL with demographics, healthy behaviors, tumor characteristics, and mitochondrial DNA copy number in breast cancer patients. The study used a sub-sample of 934 women with newly diagnosed breast cancer at M.D. Anderson from 2013 to 2018. To construct the AL score, the study used a battery of seventeen factors that represents the activity of five physiological systems: metabolic, cardiovascular, immunological, renal, and liver. RESULTS: AL was positively associated with the age of disease diagnosis (P = 0.002), and was higher in Black and Hispanic populations than White (P = 0.001 and 0.032, respectively). AL was also found more abundant in those who experienced marital dissolution (P = 0.006), lacked a college education (P = 0.045), currently smoked (P = 0.011), and had low levels of physical activity (P = 0.037) than their counterparts. The study then found that higher AL was associated with increased odds of having poorly differentiated tumors (Odds ratio (OR): 1.40, 95% confidence interval (CI): 1.28, 1.62). An additional significant association was observed between AL with estrogen receptor negative (ER-) (OR = 1.56, 95%CI: 1.02, 2.36) among Black patients. Finally, we observed a significant positive correlation between AL with leukocyte mitochondrial DNA copy number variation (P < 0.001). CONCLUSIONS: We conclude AL is influenced by selected demographics and healthy behaviors, and further is correlated with tumor characteristics and mitochondrial DNA copy number in breast cancer patients.

Correction: Shen, J.; et al. Biological Aging Marker p16INK4a in T Cells and Breast Cancer Risk. Cancers 2020, 12, 3122.

The authors wish to make the following corrections to this paper [...].

Biological Aging Marker p16INK4a in T Cells and Breast Cancer Risk.

Prior research has demonstrated that altered telomere length, a well-known marker for biological aging, is associated with various types of human cancer. However, whether such association extends to additional hallmarks of biological aging, including cellular senescence, has not been determined yet. In this two-stage study, we assessed the association between p16INK4a mRNA expression in T cells, a marker of cellular senescence, and breast cancer risk. The discovery stage included 352 breast cancer patients and 324 healthy controls. p16INK4a mRNA expression was significantly higher in individuals who were older, Black, and had family history of cancer than their counterparts in both cases and controls. p16INK4a mRNA expression also differed by marital status, annual income, and smoking status in cases. In the discovery stage, we found that increased p16INK4a mRNA expression was associated with 1.40-fold increased risk of breast cancer (OR = 1.40; 95%CI: 1.21, 1.68; p < 0.001). A marginally significant association was further observed in the validation stage with 47 cases and 48 controls using pre-diagnostic samples (OR = 1.28; 95%CI: 0.98, 2.97; p = 0.053). In addition, we found that p16INK4a mRNA expression was higher in tumors with selected aggressive characteristics (e.g., poorly differentiated and large tumors) than their counterparts. In summary, our results demonstrate that higher p16INK4a mRNA expression in T cells is a risk factor for breast cancer and further support the role of biological aging in the etiology of breast cancer development. Novelty and Impact Statements: The results from this study provide evidence that cellular senescence, a process of biological aging, plays a role in breast cancer etiology. In addition, our results also support that social demographics may modify cellular senescence and biological aging.

HIF3A DNA methylation, obesity and weight gain, and breast cancer risk among Mexican American women.

OBJECTIVE: In previous epigenome-wide association studies, Hypoxia inducible Factor 3 Alpha Subunit (HIF3A) DNA methylation has been reported to be associated with body mass index (BMI) and weight change. However, none of these studies have included Mexican Americans. METHODS: In the current study, we assessed levels of HIF3A methylation in 927 Mexican American women identified from Mano-A-Mano, the Mexican American Cohort study. RESULTS: Significantly higher methylation levels at three CpG sites (position 46801557, 46801642, and 46801699) were observed in obese women compared to non-obese women (P < 0.05). Furthermore, we found that elevated methylation levels at those three CpG sites were associated with significant weight gain (P < 0.05), defined as an increase in BMI by at least one category between the baseline and the follow-up, with a median follow-up time of 39 months. Then, using pre-diagnostic blood DNA samples, we found increased DNA methylation at CpG 46801642 to be associated with a 1.35-fold increased risk of breast cancer (Hazard Ratio (HR) = 1.35, 95% Confidence Interval (CI): 1.02, 3.01), with a median follow-up time of 127 months. Using the Cancer Genome Atlas (TCGA) data, we further found that levels of HIF3A were significantly higher-methylated and down-regulated in breast tumor than in normal tissues (P < 1 × 1012 for both). CONCLUSION: Thus, our results provide evidence to support the role of HIF3A in obesity, weight gain, and the development of breast cancer.

Homologous recombination repair capacity in peripheral blood lymphocytes and breast cancer risk.

Deficiency in homologous recombination repair (HRR) capacity is frequently observed in breast tumors. However, whether HRR deficiency is a tumor-specific biomarker or a risk factor for breast cancer is unknown. In this two-stage study, using a host cell reactivation assay, we assessed the relationship between HRR capacity in peripheral blood lymphocytes (PBLs) and breast cancer risk. The discovery stage included 152 breast cancer patients and 152 healthy controls matched on age and race. HRR capacity was found to be significantly lower in Black women than in White women among controls (P = 0.015) and cases (P = 0.012). Among cases, triple negative breast cancer patients had significantly lower HRR capacity than ER+/PR+ breast cancer patients (P = 0.006). In risk assessment, HRR capacity was found to be significantly lower in cases than in controls (P < 0.001), and decreased HRR capacity was associated with 1.42-fold increased risk of breast cancer (95% CI: 1.21, 2.53). In the validation stage, we assessed HRR capacity in a nested case-control study using pre-diagnostic samples. We found that decreased HRR capacity was associated with 1.21-fold increased risk of breast cancer (95% CI: 1.04, 4.58). In summary, our results demonstrate that decreased HRR capacity in PBLs is a risk factor for breast cancer.

Identification of metabolites in plasma for predicting survival in glioblastoma.

Circulating metabolomics profiling holds prognostic potential. However, such efforts have not been extensively carried out in glioblastoma. In this study, two-step (training and testing) metabolomics profiling was conducted from the plasma samples of 159 glioblastoma patients. Metabolomics profiling was tested for correlation with 2-year overall and disease-free survivals. Arginine, methionine, and kynurenate levels were significantly associated with 2-year overall survival in both the training and testing sets. In the combined sets, elevated levels of arginine and methionine were associated with a 34% and 37% increased probability whereas kynurenate was associated with a 55% decreased probability of 2-year overall survival. These three metabolites were also significantly associated with 2-year disease-free survival. Risk scores were generated using the linear combination of levels of these significant metabolites. Glioblastoma patients with a high-risk score exhibited a 2.41-fold decreased probability of 2-year overall survival (hazard ratio (HR) = 2.41; 95% Confidence Interval (CI) = 1.20-4.93) and a 3.17-fold decreased probability of 2-year disease free survival (HR = 3.17, 95%CI = 1.42-7.54) relative to those with a low-risk score. In conclusion, we identified a unique plasma metabolite profile that is predictive of glioblastoma prognosis.

Serum HOTAIR and GAS5 levels as predictors of survival in patients with glioblastoma.

Circulating long non-coding RNAs (lncRNAs) are a new class of cancer biomarkers. However, their significance in predicting outcomes in glioblastoma patients is unclear. We measured the levels of six known oncogenic lncRNAs-CRNDE, GAS5, H19, HOTAIR, MALAT1, and TUG1 in serum samples from 106 patients with primary glioblastoma and analyzed their association with outcomes. High levels of HOTAIR were associated with decreased probability of 2-year overall survival (adjusted hazard ratio [HR] = 2.04; 95% confidence interval [CI] = 1.08-9.76), and disease-free survival (adjusted HR = 1.82; 95% CI = 1.04-6.17). High levels of GAS5 were associated with increased probability of 2-year overall survival (adjusted HR = 0.44; 95% CI = 0.18-0.99), and disease-free survival (adjusted HR = 0.46; 95% CI = 0.16-0.98). HOTAIR and GAS5 levels could serve as reciprocal prognostic predictors of survival and disease progression in patients with glioblastoma.

Global DNA hypomethylation in leukocytes associated with glioma risk.

Global DNA hypomethylation in leukocytes has been associated with increased risk for a variety of cancers. However, the role of leukocyte global DNA hypomethylation in glioma development, if any, is largely unknown. To define this role, we performed a case-control study with 390 glioma patients and 390 controls with no known cancer. Levels of 5-methylcytosine (5-mC%), a marker for global DNA methylation, were measured in leukocyte DNA. Overall, median levels of 5-mC% were significantly lower in glioma cases than in controls (3.45 vs 3.82, P=0.001). Levels of 5-mC% differed significantly by age and sex among controls and by tumor subtype and grade among glioma cases. In multivariate analysis, lower levels of 5-mC% were associated with a 1.31-fold increased risk of glioma (odds ratio = 1.31, 95% confidence interval = 1.10-1.41). A significant dose-response trend was observed in quartile analysis (P=0.001). In an analysis further stratified by clinical characteristics at baseline, the association between lower levels of 5-mC% and glioma risk was evident only among younger participants (age <52 years), women, and those with aggressive tumor characteristics, such as glioblastoma subtype, high tumor grade (grade III or IV), and absence of IDH1 mutation. Our findings indicate that global DNA hypomethylation in leukocytes may contribute to the development of glioma and that the association is affected by age, sex, and tumor aggressiveness.

Serum microRNA profiling in patients with glioblastoma: a survival analysis.

Because circulating microRNAs (miRNAs) have drawn a great deal of attention as promising novel cancer diagnostics and prognostic biomarkers, we sought to identify serum miRNAs significantly associated with outcome in glioblastoma patients. To do this, we performed global miRNA profiling in serum samples from 106 primary glioblastoma patients. The study subjects were randomly divided into two sets: set one (n = 40) and set two (n = 66). Using a Cox regression model, 3 serum miRNAs (miR-106a-5p, miR-182, and miR-145-5p) and 5 serum miRNAs (miR-222-3p, miR-182, miR-20a-5p, miR-106a-5p, and miR-145-5p) were identified significantly associated with 2-year patient overall survival and disease-free survival (P < 0.05) in both sets and the combined set. We then created the miRNA risk scores to assess the total impact of the significant serum miRNAs on survival. The high risk scores were associated with poor patient survival (overall survival: HR = 1.92, 95% CI: 1.19, 10.23, and disease-free survival: HR = 2.03, 95%CI: 1.24, 4.28), and were independent of other clinicopathological factors. Our results suggest that serum miRNAs could serve as prognostic predictors of glioblastoma.

Global methylation of blood leukocyte DNA and risk of melanoma.

Global DNA methylation, possibly influenced by lifestyle and environmental factors, has been suggested to play an active role in carcinogenesis. However, its role in melanoma has rarely been explored. The aims of this study were to evaluate the relationship between melanoma risk and levels of 5-methylcytosine (5-mC), a marker for global DNA methylation, in blood leukocyte DNA, and to determine whether this 5-mC level is influenced by pigmentation and sun exposure. This case-control study included 540 melanoma cases and 540 healthy controls. Overall, melanoma cases had significantly lower levels of 5-mC% than healthy controls (median: 3.24 vs. 3.91, p < 0.001). The significant difference between two groups did not differ by pigmentation or sun exposure. Among healthy controls, however, those who had fair skin color (p = 0.041) or light or no tanning after prolonged sun exposure (p = 0.031) or used a sunlamp (p = 0.028) had lower levels of 5-mC% than their counterparts. In addition, those with an intermediate or high phenotypic index, an indicator of cutaneous cancer susceptibility, had 2.58-fold greater likelihood of having a low level of 5-mC% [odds ratio (OR): 2.58; 95% confidence interval (CI): 1.72, 3.96] than those with a low phenotypic index. Lower levels of 5-mC% were associated with a 1.25-fold greater risk of melanoma (OR: 1.25; 95% CI: 1.08, 1.37). A significant dose-response relationship was observed in quartile analysis (p = 0.001). Our results suggest that global hypomethylation in blood leukocyte DNA is associated with increased risk of melanoma and that the level of methylation is influenced by pigmentation and sun exposure.

Metabolomics profiling in plasma samples from glioma patients correlates with tumor phenotypes.

BACKGROUND: Tumor-based molecular biomarkers have redefined in the classification gliomas. However, the association of systemic metabolomics with glioma phenotype has not been explored yet. METHODS: In this study, we conducted two-step (discovery and validation) metabolomic profiling in plasma samples from 87 glioma patients. The metabolomics data were tested for correlation with glioma grade (high vs low), glioblastoma (GBM) versus malignant gliomas, and IDH mutation status. RESULTS: Five metabolites, namely uracil, arginine, lactate, cystamine, and ornithine, significantly differed between high- and low-grade glioma patients in both the discovery and validation cohorts. When the discovery and validation cohorts were combined, we identified 29 significant metabolites with 18 remaining significant after adjusting for multiple comparisons. Those 18 significant metabolites separated high- from low-grade glioma patients with 91.1% accuracy. In the pathway analysis, a total of 18 significantly metabolic pathways were identified. Similarly, we identified 2 and 6 metabolites that significantly differed between GBM and non-GBM, and IDH mutation positive and negative patients after multiple comparison adjusting. Those 6 significant metabolites separated IDH1 mutation positive from negative glioma patients with 94.4% accuracy. Three pathways were identified to be associated with IDH mutation status. Within arginine and proline metabolism, levels of intermediate metabolites in creatine pathway were all significantly lower in IDH mutation positive than in negative patients, suggesting an increased activity of creatine pathway in IDH mutation positive tumors. CONCLUSION: Our findings identified metabolites and metabolic pathways that differentiated tumor phenotypes. These may be useful as host biomarker candidates to further help glioma molecular classification.

Mitochondrial DNA copy number in whole blood and glioma risk: A case control study.

Alterations in mitochondrial DNA (mtDNA) copy number are observed in human gliomas. However, whether variations in mtDNA copy number in whole blood play any role in glioma carcinogenesis is still largely unknown. In current study with 395 glioma patients and 425 healthy controls, we intended to investigate the association between mtDNA copy number in whole blood and glioma risk. Overall, we found that levels of mtDNA copy number were significantly higher in glioma cases than healthy controls (mean: 1.48 vs. 1.32, P < 0.01). In both cases and controls, levels of mtDNA copy number were inversely correlated with age (P < 0.01, respectively). And in cases, newly diagnosed, glioblastoma (GBM), and high grade glioma patients had significantly lower mtDNA copy number than their counterparts (P = 0.02, P < 0.01, and P = 0.04, respectively). In the multivariate analysis, elevated mtDNA copy number levels were associated with a 1.63-fold increased risk of glioma (adjusted odds ratio (OR) = 1.63, 95% confidence interval (CI) = 1.23-2.14). In further quartile analysis, study subjects who had highest levels of mtNDA copy number had 1.75-fold increased risk of gliomas (adjOR = 1.75, 95%CI = 1.18-2.61). In brief, our findings support the role of mtDNA copy number in the glioma carcinogenesis. © 2016 Wiley Periodicals, Inc.

Obg-like ATPase 1 regulates global protein serine/threonine phosphorylation in cancer cells by suppressing the GSK3ß-inhibitor 2-PP1 positive feedback loop.

OLA1 is an Obg family P-loop NTPase that possesses both GTP- and ATP-hydrolyzing activities. Here we report that OLA1 is a GSK3ß interacting protein, and through its ATPase activity, inhibits the GSK3ß-mediated activation of protein serine/threonine phosphatase 1 (PP1). It is hypothesized that GSK3ß phosphorylates inhibitor 2 (I-2) of PP1 at Thr-72 and activates the PP1 · I-2 complex, which in turn dephosphorylates and stimulates GSK3ß, thus forming a positive feedback loop. We revealed that the positive feedback loop is normally suppressed by OLA1, and becomes over-activated under OLA1 deficiency, resulting in increased cellular PP1 activity and dephosphorylation of multiple Ser/Thr phosphoproteins, and more strikingly, decreased global protein threonine phosphorylation. Furthermore, using xenograft models of colon cancer (H116) and ovarian cancer (SKOV3), we established a correlation among downregulation of OLA1, over-activation of the positive feedback loop as indicated by under-phosphorylation of I-2, and more aggressive tumor growth. This study provides the first evidence for the existence of a GSK3ß-I-2-PP1 positive feedback loop in human cancer cells, and identifies OLA1 as an endogenous suppressor of this signaling motif.

Peripheral blood mitochondrial DNA copy number, length heteroplasmy and breast cancer risk: a replication study.

Oxidative stress has consistently been linked to breast carcinogenesis, and mitochondria play a significant role in regulating reactive oxygen species generation. In our previous study, we found that increased levels of mitochondrial DNA (mtDNA) copy number and the presence of mitochondrial length heteroplasmies in the hypervariable (HV) regions 1 and 2 (HV1 and HV2) in peripheral blood are associated with increased risk of breast cancer. In current study with 1000 breast cancer cases and 1000 healthy controls, we intended to replicate our previous findings. Overall, levels of mtDNA copy number were significantly higher in breast cancer cases than healthy controls (mean: 1.17 versus 0.94, P < 0.001). In the multivariate linear regression analysis, increased mtDNA copy number levels were associated with a 1.32-fold increased risk of breast cancer [adjusted odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.15-1.67]. Breast cancer cases were more likely to have HV1 and HV2 region length heteroplasmies than healthy controls (P < 0.001, respectively). The existence of HV1 and HV2 length heteroplasmies was associated with 2.01- and 1.63-folds increased risk of breast cancer (for HV1: OR = 2.01, 95% CI = 1.66-2.42; for HV2: OR = 1.63, 95% CI = 1.34-1.92). Additionally, joint effects among mtDNA copy number, HV1 and HV2 length heteroplasmies were observed. Our results are consistent with our previous findings and further support the roles of mtDNA copy number and mtDNA length heteroplasmies that may play in the development of breast cancer.

OLA1 regulates protein synthesis and integrated stress response by inhibiting eIF2 ternary complex formation.

Translation is a fundamental cellular process, and its dysregulation can contribute to human diseases such as cancer. During translation initiation the eukaryotic initiation factor 2 (eIF2) forms a ternary complex (TC) with GTP and the initiator methionyl-tRNA (tRNAi), mediating ribosomal recruitment of tRNAi. Limiting TC availability is a central mechanism for triggering the integrated stress response (ISR), which suppresses global translation in response to various cellular stresses, but induces specific proteins such as ATF4. This study shows that OLA1, a member of the ancient Obg family of GTPases, is an eIF2-regulatory protein that inhibits protein synthesis and promotes ISR by binding eIF2, hydrolyzing GTP, and interfering with TC formation. OLA1 thus represents a novel mechanism of translational control affecting de novo TC formation, different from the traditional model in which phosphorylation of eIF2α blocks the regeneration of TC. Depletion of OLA1 caused a hypoactive ISR and greater survival in stressed cells. In vivo, OLA1-knockdown rendered cancer cells deficient in ISR and the downstream proapoptotic effector, CHOP, promoting tumor growth and metastasis. Our work suggests that OLA1 is a novel translational GTPase and plays a suppressive role in translation and cell survival, as well as cancer growth and progression.