bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2022–11–27
three papers selected by
Linda Chan, Yale University
  1. Metabolic symbiosis in pancreatic cancer.
  2. Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells.
  3. Mitophagy bridges DNA sensing with metabolic adaption to expand lung cancer stem-like cells.
  1. Nat Cancer. 2022 Nov 21.
    Metabolic symbiosis in pancreatic cancer.
    Dylan Gerard Ryan, Christian Frezza.
      
    DOI:  https://doi.org/10.1038/s43018-022-00454-2
  2. Nat Cancer. 2022 Nov 21.
    Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells.
    Christopher J Halbrook, Galloway Thurston, Seth Boyer, Cecily Anaraki, Jennifer A Jiménez, Amy McCarthy, Nina G Steele, Samuel A Kerk, Hanna S Hong, Lin Lin, Fiona V Law, Catherine Felton, Lorenzo Scipioni, Peter Sajjakulnukit, Anthony Andren, Alica K Beutel, Rima Singh, Barbara S Nelson, Fran Van Den Bergh, Abigail S Krall, Peter J Mullen, Li Zhang, Sandeep Batra, Jennifer P Morton, Ben Z Stanger, Heather R Christofk, Michelle A Digman, Daniel A Beard, Andrea Viale, Ji Zhang, Howard C Crawford, Marina Pasca di Magliano, Claus Jorgensen, Costas A Lyssiotis.
      The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.
    DOI:  https://doi.org/10.1038/s43018-022-00463-1
  3. EMBO Rep. 2022 Nov 23. e54006
    Mitophagy bridges DNA sensing with metabolic adaption to expand lung cancer stem-like cells.
    Zhen Liu, Shan Shan, Zixin Yuan, Fengying Wu, Ming Zheng, Ying Wang, Jun Gui, Wei Xu, Chunhong Wang, Tao Ren, Zhenke Wen.
      While previous studies have identified cancer stem-like cells (CSCs) as a crucial driver for chemoresistance and tumor recurrence, the underlying mechanisms for populating the CSC pool remain unclear. Here, we identify hypermitophagy as a feature of human lung CSCs, promoting metabolic adaption via the Notch1-AMPK axis to drive CSC expansion. Specifically, mitophagy is highly active in CSCs, resulting in increased mitochondrial DNA (mtDNA) content in the lysosome. Lysosomal mtDNA acts as an endogenous ligand for Toll-like receptor 9 (TLR9) that promotes Notch1 activity. Notch1 interacts with AMPK to drive lysosomal AMPK activation by inducing metabolic stress and LKB1 phosphorylation. This TLR9-Notch1-AMPK axis supports mitochondrial metabolism to fuel CSC expansion. In patient-derived xenograft chimeras, targeting mitophagy and TLR9-dependent Notch1-AMPK pathway restricts tumor growth and CSC expansion. Taken together, mitochondrial hemostasis is interlinked with innate immune sensing and Notch1-AMPK activity to increase the CSC pool of human lung cancer.
    Keywords:  AMPK; Notch1; TLR9; cancer stem-like cell; mitophagy
    DOI:  https://doi.org/10.15252/embr.202154006
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