LAMC2 Regulates Key Transcriptional and Targetable Effectors to Support Pancreatic Cancer Growth DOI
Oihane Erice, Shruthi Narayanan, Iker Feliu

et al.

Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 29(6), P. 1137 - 1154

Published: Jan. 6, 2023

The identification of pancreatic ductal adenocarcinoma (PDAC) dysregulated genes may unveil novel molecular targets entering inhibitory strategies. Laminins are emerging as potential in PDAC given their role diagnostic and prognostic markers. Here, we investigated the cellular, functional, clinical relevance LAMC2 its regulated network, with ultimate goal identifying therapies.LAMC2 expression was analyzed tissues, a panel human mouse cell lines, genetically engineered model. Genetic perturbation 2D, 3D, vivo allograft xenograft models done. Expression profiling network performed by RNA-sequencing, publicly available gene datasets from experimental studies examined to query relevance. Dual inhibition pharmacologically targetable LAMC2-regulated effectors investigated.LAMC2 consistently upregulated well specimens, associated tumor grade survival. impaired cycle, induced apoptosis, sensitized MEK1/2 inhibitors (MEK1/2i). A featured PDAC, including both classical quasi-mesenchymal subtypes, contained downstream transcriptionally shared KRAS signaling pathway. functional FOSL1-AXL axis via AKT phosphorylation. Furthermore, genetic or pharmacological AXL elicited synergistic antiproliferative effect combination MEK1/2is that consistent across 2D 3D models, primary patient-derived organoids.LAMC2 is target regulates transcriptional unveils dual drug for cancer treatment.

Language: Английский

Pancreatic cancer: Advances and challenges DOI Creative Commons
Christopher J. Halbrook, Costas A. Lyssiotis, Marina Pasca di Magliano

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(8), P. 1729 - 1754

Published: April 1, 2023

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis and progression. tumors are characterized by a complex microenvironment that orchestrates metabolic alterations supports milieu interactions among various cell types within this niche. In review, we highlight foundational studies driven our understanding these processes. We further discuss recent technological advances continue to expand complexity. posit clinical translation research endeavors will enhance currently dismal survival rate recalcitrant disease.

Language: Английский

Citations

563
Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies DOI Creative Commons
Zhefang Wang, Fanyu Liu, Ningbo Fan

et al.

Frontiers in Oncology, Journal Year: 2020, Volume and Issue: 10

Published: Oct. 26, 2020

Metabolism Rewiring is a hallmark of cancer. As one the most abundant free amino acids in human blood, glutamine supports bioenergetics and biosynthesis, tumor growth, production antioxidants through glutaminolysis In dependent cancer cells, more than half TCA metabolites are derived from glutamine. Glutaminolysis controls process converting into cycle regulation multiple enzymes, while glutaminase shows importance as very first step this process. Targeting inhibition emerges promising strategy to disrupt metabolism progression. Here, we review role metastasis. Furthermore, highlight inhibitor based metabolic therapy their applications clinical set up.

Language: Английский

Citations

151
Harnessing metabolic dependencies in pancreatic cancers DOI
Joel Encarnación-Rosado, Alec C. Kimmelman

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2021, Volume and Issue: 18(7), P. 482 - 492

Published: March 19, 2021

Language: Английский

Citations

125
The Epithelial–Mesenchymal Transition at the Crossroads between Metabolism and Tumor Progression DOI Open Access
Monica Fedele, Riccardo Sgarra, Sabrina Battista

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(2), P. 800 - 800

Published: Jan. 12, 2022

The transition between epithelial and mesenchymal phenotype is emerging as a key determinant of tumor cell invasion metastasis. It plastic process in which cells first acquire the ability to invade extracellular matrix migrate into bloodstream via transdifferentiation cells, phenomenon known epithelial–mesenchymal (EMT), then reacquire phenotype, reverse called mesenchymal–epithelial (MET), colonize new organ. During all metastatic stages, metabolic changes, give cancer adapt increased energy demand withstand hostile environment, are also important determinants successful progression. In this review, we describe complex interaction EMT metabolism during First, outline main connections two processes, with particular emphasis on role stem LncRNAs. Then, focus some specific cancers, such breast, lung, thyroid cancer.

Language: Английский

Citations

123
RNA N6-methyladenosine reader IGF2BP2 promotes lymphatic metastasis and epithelial-mesenchymal transition of head and neck squamous carcinoma cells via stabilizing slug mRNA in an m6A-dependent manner DOI Creative Commons
Dan Yu, Min Pan,

Yanshi Li

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2022, Volume and Issue: 41(1)

Published: Jan. 3, 2022

Lymph node metastasis is the main cause of poor prognosis head and neck squamous carcinoma (HNSCC) patients. N6-methyladenosine (m6A) RNA modification an emerging epigenetic regulatory mechanism for gene expression, as a novel m6A reader protein, IGF2BP2 has been implicated in tumor progression metastasis. However, not much currently known about functional roles HNSCC, whether regulates lymphatic through HNSCC remains to be determined.The expression overall survival (OS) probability m6A-related regulators were analyzed with The Cancer Genome Atlas (TCGA) dataset GEPIA website tool, respectively. levels measured tissues normal adjacent tissues. To study effects on cell vitro vivo, gain- loss- function methods employed. RIP, MeRIP, luciferase reporter mRNA stability assays performed explore HNSCC.We investigated 20 discovered that only overexpression was associated OS independent prognostic factor Additionally, we demonstrated overexpressed tissues, significantly correlated prognosis. Functional studies have shown promotes both migration well invasion via epithelial-mesenchymal transition (EMT) process vitro, knockdown inhibited lymphangiogenesis vivo. Mechanistic investigations revealed Slug, key EMT-related transcriptional factor, direct target IGF2BP2, essential IGF2BP2-regulated EMT HNSCC. Furthermore, recognizes binds site coding sequence (CDS) region Slug its stability.Collectively, our uncovers oncogenic role potential which serves reader, controlling suggesting may act therapeutic biomarker patients

Language: Английский

Citations

88
The epithelial–mesenchymal plasticity landscape: principles of design and mechanisms of regulation DOI
Jef Haerinck, Steven Goossens, Geert Berx

et al.

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(9), P. 590 - 609

Published: May 11, 2023

Language: Английский

Citations

71
Metabolic heterogeneity in cancer DOI
Margherita Demicco, Xiao‐Zheng Liu, Katharina Leithner

et al.

Nature Metabolism, Journal Year: 2024, Volume and Issue: 6(1), P. 18 - 38

Published: Jan. 24, 2024

Language: Английский

Citations

58
Molecular profile of metastasis, cell plasticity and EMT in pancreatic cancer: a pre-clinical connection to aggressiveness and drug resistance DOI

Zhenli Guo,

Milad Ashrafizadeh, Wei Zhang

et al.

Cancer and Metastasis Reviews, Journal Year: 2023, Volume and Issue: 43(1), P. 29 - 53

Published: July 15, 2023

Language: Английский

Citations

46
Targeting pancreatic cancer metabolic dependencies through glutamine antagonism DOI Creative Commons
Joel Encarnación-Rosado, Albert S.W. Sohn,

Douglas E. Biancur

et al.

Nature Cancer, Journal Year: 2023, Volume and Issue: 5(1), P. 85 - 99

Published: Oct. 9, 2023

Abstract Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. Early attempts inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming therapeutic resistance. Here, we demonstrated that treating PDAC with a antagonist, 6-diazo-5-oxo- l -norleucine (DON), led crisis vitro. In addition, observed profound decrease tumor growth several vivo models sirpiglenastat (DRP-104), pro-drug version of DON was designed circumvent DON-associated toxicity. We found extracellular signal-regulated kinase (ERK) signaling is increased as compensatory mechanism. Combinatorial treatment DRP-104 trametinib significant increase survival syngeneic model PDAC. These proof-of-concept studies suggested broadly targeting could provide avenue for The combination an ERK pathway inhibitor further improve the outcome.

Language: Английский

Citations

45
The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism DOI Creative Commons
Mona Nazemi, Bian Yanes, Montserrat Llanses Martinez

et al.

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(1), P. e3002406 - e3002406

Published: Jan. 16, 2024

Breast tumours are embedded in a collagen I-rich extracellular matrix (ECM) network, where nutrients scarce due to limited blood flow and elevated tumour growth. Metabolic adaptation is required for cancer cells endure these conditions. Here, we demonstrated that the presence of ECM supported growth invasive breast cells, but not non-transformed mammary epithelial under amino acid starvation, through mechanism macropinocytosis-dependent uptake. Importantly, showed this behaviour was acquired during carcinoma progression. internalisation, followed by lysosomal degradation, contributed up-regulation intracellular levels several acids, most notably tyrosine phenylalanine. This resulted catabolism on leading increased fumarate levels, potentially feeding into tricarboxylic (TCA) cycle. Interestingly, pathway ECM-dependent cell migration as knockdown p-hydroxyphenylpyruvate hydroxylase-like protein (HPDL), third enzyme pathway, opposed motility both 2D 3D systems, without affecting proliferation plastic. Finally, high HPDL expression correlated with poor prognosis patients. Collectively, our results highlight microenvironment (TME) represents an alternative source support regulating phenylalanine metabolism.

Language: Английский

Citations

23