Functional Genomics In Vivo Reveal Metabolic Dependencies of Pancreatic Cancer Cells

Zhu, Xiphias Ge; Chudnovskiy, Aleksey; Baudrier, Lou; Prizer, Benjamin; Liu, Yuyang; Ostendorf, Benjamin N.; Yamaguchi, Norihiro; Arab, Abolfazl; Tavora, Bernardo; Timson, Rebecca C.; Heissel, Søren; Stanchina, Elisa de; Molina, Henrik; Victora, Gabriel D.; Goodarzi, Hani; Birsoy, Kıvanç

doi:10.1016/j.cmet.2020.10.017

Cited by 84 publications

(79 citation statements)

References 49 publications

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“…Guide scores were calculated as median log 2 fold change in the abundance between the initial and final population of that sgRNA similar to standard CRISPR screens. The KP PDAC patient derived xenograft (PDX) model for in vivo competition assay was described previously 51 . Briefly, low passage PDX pancreatic tumor was chopped finely and digested with collagenase type IV for 30 min.…”

Section: Methodsmentioning

confidence: 99%

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Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia

García‐Bermúdez

Prasad

Baudrier

et al. 2021

Preprint

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Stress-adaptive mechanisms enable tumor cells to overcome metabolic constraints in nutrient and oxygen poor tumors. Aspartate is an endogenous metabolic limitation under hypoxic conditions, but the nature of the adaptive mechanisms that contribute to aspartate availability and hypoxic tumor growth are poorly understood. Here, using a combination of metabolomics and CRISPR-based genetic screens, we identify GOT2-catalyzed mitochondrial aspartate synthesis as an essential metabolic dependency for the proliferation of pancreatic tumor cells under hypoxic culture conditions. In contrast, GOT2-catalyzed aspartate synthesis is dispensable for pancreatic tumor formation in vivo. The dependence of pancreatic tumor cells on aspartate synthesis is bypassed in part by a hypoxia-induced potentiation of extracellular protein scavenging via macropinocytosis. This effect is mutant KRas-dependent, and is mediated by hypoxia inducible factor 1 (HIF1A) and its canonical target carbonic anhydrase-9 (CA9) through the cooption of the bicarbonate-macropinocytosis signaling axis. Our findings reveal high plasticity of aspartate metabolism and define an adaptive regulatory role for macropinocytosis by which mutant KRas tumors can overcome nutrient deprivation under hypoxic conditions.

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Section: Methodsmentioning

confidence: 99%

“…The KP PDAC patient derived xenograft (PDX) model for in vivo competition assay was described previously 51 . Briefly, low passage PDX pancreatic tumor was chopped finely and digested with collagenase type IV for 30 min.…”

Section: Sgrna Competition Assay In Vitro and In Vivomentioning

confidence: 99%

Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia

García‐Bermúdez

Prasad

Baudrier

et al. 2021

Preprint

Self Cite

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“…Therefore, understanding of how metabolic reprogramming can impair ADCP function or how chronic therapeutic antibody-mediated ADCP stimulation can influence acquired mechanisms of trastuzumab or DS8201a resistance would be valuable. Autophagy, a metabolic reprogramming process increased in highly hypoxic nutrient-deprived tumors such as pancreatic adenocarcinomas [ 111 ], has recently been shown to increase immune suppression [ 112 , 113 ]. It is further unclear how autophagy suppresses the immune system, although Yamamoto et al suggest that autophagy increases immunosuppression through reduced MCH-I expression [ 112 ].…”

Section: Igf1r Pathway: Lessons To Learn For Adequate Drug Development In Ras Wild-type Mcrc Patientsmentioning

confidence: 99%

“…It is further unclear how autophagy suppresses the immune system, although Yamamoto et al suggest that autophagy increases immunosuppression through reduced MCH-I expression [ 112 ]. Other authors indicate that autophagy can decrease TNFα-dependent cell death by immune CD8+ T-cells [ 113 ]. We are tempted to speculate that continuous ADCP stimulation (either by cancer-mediated autophagy metabolic reprogramming or antibody-mediated stimuli) induces LAP-dependent M2 polarization [ 114 ] and PD-L1 and IDO-1 expression [ 115 ] (see Figure 2 ).…”

Section: Igf1r Pathway: Lessons To Learn For Adequate Drug Development In Ras Wild-type Mcrc Patientsmentioning

confidence: 99%

Lessons to Learn for Adequate Targeted Therapy Development in Metastatic Colorectal Cancer Patients

Oliveres

Pesántez

Maurel

2021

IJMS

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Insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase that regulates cell growth and proliferation. Upregulation of the IGF1R pathway constitutes a common paradigm shared with other receptor tyrosine kinases such as EGFR, HER2, and MET in different cancer types, including colon cancer. The main IGF1R signaling pathways are PI3K-AKT and MAPK-MEK. However, different processes, such as post-translational modification (SUMOylation), epithelial-to-mesenchymal transition (EMT), and microenvironment complexity, can also contribute to intrinsic and acquired resistance. Here, we discuss new strategies for adequate drug development in metastatic colorectal cancer patients.

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“…As a highly selective quality control, mechanism autophagy is the key to maintaining homeostasis in physiological and pathological conditions [12], such as adapting to metabolic stress, removing dangerous cargo, and renovating during differentiation and development, genomic prevention damage [13]. However, more and more evidence indicated that hat autophagy could also help tumor occurrence, maintenance, and development [14]. In pancreatic cancer [15], autophagy is a metabolic requirement for cancer cells' immune evasion, allowing tumors to achieve optimal proliferation in vitro and vivo.…”

Section: Introductionmentioning

confidence: 99%

Seven Autophagy-Related lncRNAs Associated With Clinical Prognosis in Hepatocellular Carcinoma.

Zhou

Liu

Zhang

et al. 2021

Preprint

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Background: LncRNA may be involved in the occurrence, metastasis, and chemical reaction of hepatocellular carcinoma (HCC) through various pathways associated with autophagy. Therefore, it is urgent to reveal more autophagy-related lncRNAs, explore these lncRNAs' clinical significance, and find new targeted treatment strategies. Methods: In our study, RNA-seq and clinical data of normal and HCC patients were obtained from the TCGA database, and autophagy genes were obtained from the human autophagy database. Results: The risk prediction model containing seven autophagy-related lncRNAs was constructed. Overall survival (OS) curves show that the high-risk group patients significantly shorter than the low-risk group (P=2.292e-10), and the five years survival rate of the high-risk group (HR 0.286, 95%CI 0.199-0.411) is less than half of the low-risk group (HR 0.694, 95%CI 0.547-0.77). Univariate Cox regression indicated that risk score of the risk prediction model (P<0.001, 95%CI 1.210-1.389 ), T (P<0.001, 95%CI 1.443-2.287), and stage (P<0.001 ,95%CI 1.466-2.408 ) were independent prognostic indicators. However, only the risk score remains the independent prognostic indicator(P<0.001, 95%CI 1.197-1.400 ) based on the multivariate analysis. This risk model's prediction efficiency is significantly higher than other clinicopathological factors for 1-, 3- and 5-year survival rate prediction (AUC are 0.853, 0.794, and 0.764, respectively). Remarkably, the 7 autophagy-related lncRNAs may participate in Spliceosome, Cell cycle, RNA transport, DNA replication, and mRNA surveillance pathway and be related to the biological process of RNA splicing and mRNA splicing. Conclusion: In conclusion, the 7 autophagy-related lncRNAs might be promising prognostic and therapeutic targets for HCC.

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Functional Genomics In Vivo Reveal Metabolic Dependencies of Pancreatic Cancer Cells

Cited by 84 publications

References 49 publications

Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia

Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia

Lessons to Learn for Adequate Targeted Therapy Development in Metastatic Colorectal Cancer Patients

Seven Autophagy-Related lncRNAs Associated With Clinical Prognosis in Hepatocellular Carcinoma.

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