Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer

Gabitova-Cornell, Linara; Surumbayeva, Aizhan; Peri, Suraj; Franco‐Barraza, Janusz; Restifo, Diana; Weitz, Nicole A.; Ogier, Charline; Goldman, Aaron R.; Hartman, Tiffiney R.; Francescone, Ralph; Tan, Yin Fei; Nicolas, Émmanuelle; Shah, Neelima; Handorf, Elizabeth A.; Cai, Kathy Q.; O’Reilly, Alana M.; Sloma, Ido; Chiaverelli, Rachel; Moffitt, Richard A.; Khazak, Vladimir; Fang, Carolyn Y.; Golemis, Erica A.; Cukierman, Edna; Astsaturov, Igor

doi:10.1016/j.ccell.2020.08.015

Cited by 131 publications

(137 citation statements)

References 82 publications

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“…Other lipid metabolites, such as cholesterol, were described to regulate PDAC differentiation. Other than the correlation with reduced cholesterol levels in basal-like PDAC subtypes, a sophisticated study of Gabitova-Cornell et al demonstrated that inhibition of cholesterol biosynthesis drives the epithelial-to-mesenchymal transition (EMT) of pancreatic tumor cells and the establishment of a more aggressive tumor phenotype [ 38 ]. Though it has been shown that sphingolipids, including the two central bioactive lipids, ceramide and sphingosine-1-phosphate (S1P), have opposing roles in regulating cancer cell death and survival by evading chemoresistance [ 39 ], cellular and molecular determinants regulating the selectivity of one sphingolipid metabolite over another are poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Plasma Metabolome Profiling Identifies Metabolic Subtypes of Pancreatic Ductal Adenocarcinoma

Mahajan

Alnatsha

et al. 2021

Cells

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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Developing biomarkers for early detection and chemotherapeutic response prediction is crucial to improve the dismal prognosis of PDAC patients. However, molecular cancer signatures based on transcriptome analysis do not reflect intratumoral heterogeneity. To explore a more accurate stratification of PDAC phenotypes in an easily accessible matrix, plasma metabolome analysis using MxP® Global Profiling and MxP® Lipidomics was performed in 361 PDAC patients. We identified three metabolic PDAC subtypes associated with distinct complex lipid patterns. Subtype 1 was associated with reduced ceramide levels and a strong enrichment of triacylglycerols. Subtype 2 demonstrated increased abundance of ceramides, sphingomyelin and other complex sphingolipids, whereas subtype 3 showed decreased levels of sphingolipid metabolites in plasma. Pathway enrichment analysis revealed that sphingolipid-related pathways differ most among subtypes. Weighted correlation network analysis (WGCNA) implied PDAC subtypes differed in their metabolic programs. Interestingly, a reduced expression among related pathway genes in tumor tissue was associated with the lowest survival rate. However, our metabolic PDAC subtypes did not show any correlation to the described molecular PDAC subtypes. Our findings pave the way for further studies investigating sphingolipids metabolisms in PDAC.

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Section: Discussionmentioning

confidence: 99%

Plasma Metabolome Profiling Identifies Metabolic Subtypes of Pancreatic Ductal Adenocarcinoma

Mahajan

Alnatsha

et al. 2021

Cells

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“…By using a GEMM driven by KRAS G12D mutation and homozygous TP53 loss, a recent study demonstrated that inhibition of cholesterol biosynthesis with statins, a widely used inhibitor of the mevalonate pathway, or NAD(P)-dependent steroid dehydrogenase-like enzyme inhibitor can switch glandular pancreatic carcinomas to a basal phenotype. 202 Loss of function of TP53 can drive tumorigenesis via downregulation of cholesterol transporter gene ATP-binding cassette subfamily A member 1 and activation of PI3K/sterol regulatory element-binding protein 2 (SREBP2) maturation. Consequently, the mevalonate pathway, which is responsible for cholesterol and sterol biosynthesis, is upregulated.…”

Section: Metabolism Dysregulation In Pancreatic Cancermentioning

confidence: 99%

The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives

Wang

Zheng

Yang

et al. 2021

Sig Transduct Target Ther

200

128

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Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence. Furthermore, it is usually diagnosed at an advanced stage with a very dismal prognosis. Due to the high heterogeneity, metabolic reprogramming, and dense stromal environment associated with pancreatic cancer, patients benefit little from current conventional therapy. Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification, thus expanding clinical therapeutic options. In this review, we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression. We further discuss potential biomarkers for pancreatic cancer diagnosis, prediction, and surveillance based on novel liquid biopsies. We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models. Finally, we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.

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“…In PDAC patients, cholesterol biosynthesis is associated with a more differentiated phenotype (classical subtype), while high LDLR expression correlates with a higher risk of tumour recurrence. Interestingly, inhibition of cholesterol synthesis induced a mesenchymal phenotype [ 75 ] while blocking cholesterol uptake via the knock-down of LDLR was able to sensitise PDAC cells to chemotherapy [ 76 , 77 ].…”

Section: Metabolic Reprogramming In Pdacmentioning

confidence: 99%

Molecular and Metabolic Subtypes Correspondence for Pancreatic Ductal Adenocarcinoma Classification

Espiau-Romera

Courtois

Parejo-Alonso

et al. 2020

JCM

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Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is an extremely lethal disease due to late diagnosis, aggressiveness and lack of effective therapies. Considering its intrinsic heterogeneity, patient stratification models based on transcriptomic and genomic signatures, with partially overlapping subgroups, have been established. Besides molecular alterations, PDAC tumours show a strong desmoplastic response, resulting in profound metabolic reprogramming involving increased glucose and amino acid consumption, as well as lipid scavenging and biosynthesis. Interestingly, recent works have also revealed the existence of metabolic subtypes with differential prognosis within PDAC, which correlated to defined molecular subclasses in patients: lipogenic subtype correlated with a classical/progenitor signature, while glycolytic tumours associated with the highly aggressive basal/squamous profile. Bioinformatic analyses have demonstrated that the representative genes of each metabolic subtype are up-regulated in PDAC samples and predict patient survival. This suggests a relationship between the genetic signature, metabolic profile, and aggressiveness of the tumour. Considering all this, defining metabolic subtypes represents a clear opportunity for patient stratification considering tumour functional behaviour independently of their mutational background.

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Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer

Cited by 131 publications

References 82 publications

Plasma Metabolome Profiling Identifies Metabolic Subtypes of Pancreatic Ductal Adenocarcinoma

Plasma Metabolome Profiling Identifies Metabolic Subtypes of Pancreatic Ductal Adenocarcinoma

The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives

Molecular and Metabolic Subtypes Correspondence for Pancreatic Ductal Adenocarcinoma Classification

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