TGFβ Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer : TGFβ Induced EMT in PDAC
Rajagopal, Meena U. (Georgetown University Medical Center)
Bansal, Shivani (Georgetown University Medical Center)
Kaur, Prabhjit (Khalsa College)
Jain, Shreyans K. (Banaras Hindu University)
Altadill, Tatiana (Vall d'Hebron Institut de Recerca (VHIR))
Hinzman, Charles P. (Georgetown University Medical Center)
Li, Yaoxiang (Georgetown University Medical Center)
Moulton, Joanna (Georgetown University Medical Center)
Singh, Baldev (Georgetown University Medical Center)
Bansal, Sunil (Georgetown University Medical Center)
Chauthe, Siddheshwar Kisan (National Institute of Pharmaceutical Education and Research)
Singh, Rajbir (Khalsa College)
Banerjee, Partha P. (Georgetown University Medical Center)
Mapstone, Mark (University of California)
Fiandaca, Massimo S. (University of California)
Federoff, Howard J. (University of California)
Unger, Keith (Med-Star Georgetown University Hospital)
Smith, Jill P. (Georgetown University Medical Center)
Cheema, Amrita K. (Georgetown University Medical Center)
Universitat Autònoma de Barcelona

Data:	2021
Resum:	Pancreatic cancer is an aggressive disease with most patients diagnosed at late stages resulting in poor outcomes. While it is known that pancreatic tumor cells undergo epithelial to mesenchymal transition, the metabolic alterations accompanying that transition are not characterized. This study leveraged a metabolomics approach to understand the small molecule and biochemical perturbations that can be targeted for designing strategies for improving outcomes in pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFβ), in imparting an aggressive phenotype to PDAC is well documented, the underlying biochemical pathway perturbations driving this behaviour have not been elucidated. We used high-resolution mass spectrometry (HRMS) based molecular phenotyping approach in order to delineate metabolic changes concomitant to TGFβ-induced EMT in pancreatic cancer cells. Strikingly, we observed robust changes in amino acid and energy metabolism that may contribute to tumor invasion and metastasis. Somewhat unexpectedly, TGFβ treatment resulted in an increase in intracellular levels of retinoic acid (RA) that in turn resulted in increased levels of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (COL1). These findings were further validated in plasma samples obtained from patients with resectable pancreatic cancer. Taken together, these observations provide novel insights into small molecule dysregulation that triggers a molecular cascade resulting in increased EMT-like changes in pancreatic cancer cells, a paradigm that can be potentially targeted for better clinical outcomes.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Epithelial mesenchymal transition ; Pancreatic cancer ; TGF beta ; Tumor microenvironment ; 9-cis retinoic acidPANC-1 cells
Publicat a:	Cancers, Vol. 13 (december 2021) , ISSN 2072-6694

DOI: 10.3390/cancers13246204
PMID: 34944824

18 p, 3.2 MB

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