USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer

In this study, Hou et al. set out to study the molecular mechanism underlying therapy resistance to KRAS inhibitors. Using a PDAC mouse model engineered with an inducible oncogenic KRAS (KRAS*) allele, the authors identified USP21, a protein deubiquitinase, as a driver of KRAS*-independent PDAC growth that occurs via induction of macropinocytosis.

[1]  R. Andersson,et al.  The actual 5-year survivors of pancreatic ductal adenocarcinoma based on real-world data , 2020, Scientific Reports.

[2]  D. Sabatini,et al.  Nutrient regulation of mTORC1 at a glance , 2019, Journal of Cell Science.

[3]  R. DePinho,et al.  USP21 deubiquitinase promotes pancreas cancer cell stemness via Wnt pathway activation , 2019, Genes & development.

[4]  E. Petricoin,et al.  Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer , 2019, Nature Medicine.

[5]  S. Hanash,et al.  Syndecan1 is a critical mediator of macropinocytosis in pancreatic cancer , 2019, Nature.

[6]  J. Asara,et al.  Ex vivo and in vivo stable isotope labelling of central carbon metabolism and related pathways with analysis by LC–MS/MS , 2019, Nature Protocols.

[7]  J. Yap,et al.  Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers , 2019, Nature Medicine.

[8]  M. V. Recouvreux,et al.  Macropinocytosis: A Metabolic Adaptation to Nutrient Stress in Cancer , 2017, Front. Endocrinol..

[9]  N. Hay,et al.  Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? , 2016, Nature Reviews Cancer.

[10]  D. Tuveson,et al.  The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1 , 2015, Cell.

[11]  K. Ross,et al.  Transcriptional control of the autophagy-lysosome system in pancreatic cancer , 2015, Nature.

[12]  S. Clare,et al.  Ubiquitin Specific Protease 21 Is Dispensable for Normal Development, Hematopoiesis and Lymphocyte Differentiation , 2015, PloS one.

[13]  H. Arai,et al.  Small GTPases and phosphoinositides in the regulatory mechanisms of macropinosome formation and maturation , 2014, Front. Physiol..

[14]  Shan Jiang,et al.  Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer , 2014, Cell.

[15]  Joseph Rosenbluh,et al.  KRAS and YAP1 Converge to Regulate EMT and Tumor Survival , 2014, Cell.

[16]  Christian M. Metallo,et al.  Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells , 2013, Nature.

[17]  Gerald C. Chu,et al.  Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism , 2012, Cell.

[18]  J. Asara,et al.  A positive/negative ion–switching, targeted mass spectrometry–based metabolomics platform for bodily fluids, cells, and fresh and fixed tissue , 2012, Nature Protocols.

[19]  Marc Liesa,et al.  Pancreatic cancers require autophagy for tumor growth. , 2011, Genes & development.

[20]  S. Gygi,et al.  Defining the Human Deubiquitinating Enzyme Interaction Landscape , 2009, Cell.

[21]  E. Mandelkow,et al.  The tau of MARK: a polarized view of the cytoskeleton. , 2009, Trends in biochemical sciences.

[22]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[23]  R. DePinho,et al.  Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. , 2003, Genes & development.

[24]  M. Daly,et al.  PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes , 2003, Nature Genetics.