bims-lymeca Biomed News
on Lysosome metabolism in cancer
Issue of 2022–06–26
three papers selected by
Harilaos Filippakis, University of New England
  1. Past, present, and future perspectives of transcription factor EB (TFEB): mechanisms of regulation and association with disease.
  2. The central role of mTORC1 in amino acid sensing.
  3. Targeting autophagy as a therapeutic strategy against pancreatic cancer.
  1. Cell Death Differ. 2022 Jun 23.
    Past, present, and future perspectives of transcription factor EB (TFEB): mechanisms of regulation and association with disease.
    Anderson Tan, Renuka Prasad, Chaerin Lee, Eek-Hoon Jho.
      Transcription factor EB (TFEB), a member of the MiT/TFE family of basic helix-loop-helix leucine zipper transcription factors, is an established central regulator of the autophagy/lysosomal-to-nucleus signaling pathway. Originally described as an oncogene, TFEB is now widely known as a regulator of various processes, such as energy homeostasis, stress response, metabolism, and autophagy-lysosomal biogenesis because of its extensive involvement in various signaling pathways, such as mTORC1, Wnt, calcium, and AKT signaling pathways. TFEB is also implicated in various human diseases, such as lysosomal storage disorders, neurodegenerative diseases, cancers, and metabolic disorders. In this review, we present an overview of the major advances in TFEB research over the past 30 years, since its description in 1990. This review also discusses the recently discovered regulatory mechanisms of TFEB and their implications for human diseases. We also summarize the moonlighting functions of TFEB and discuss future research directions and unanswered questions in the field. Overall, this review provides insight into our understanding of TFEB as a major molecular player in human health, which will take us one step closer to promoting TFEB from basic research into clinical and regenerative applications.
    DOI:  https://doi.org/10.1038/s41418-022-01028-6
  2. Cancer Res. 2022 Jun 24. pii: canres.4403.2021. [Epub ahead of print]
    The central role of mTORC1 in amino acid sensing.
    Shusheng Yue, Guanya Li, Shanping He, Tingting Li.
      The mechanistic target of rapamycin (mTOR) is a master regulator of cell growth that controls cell homeostasis in response to nutrients, growth factors, and other environmental cues. Recent studies have emphasized the importance of lysosomes as a hub for nutrient sensing, especially amino acid sensing by mTORC1. This review highlights recent advances in understanding the amino acid-mTORC1 signaling axis and the role of mTORC1 in cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-4403
  3. J Gastroenterol. 2022 Jun 21.
    Targeting autophagy as a therapeutic strategy against pancreatic cancer.
    Keisuke Yamamoto, Dosuke Iwadate, Hiroyuki Kato, Yousuke Nakai, Keisuke Tateishi, Mitsuhiro Fujishiro.
      Macroautophagy (hereafter autophagy) is a catabolic process through which cytosolic components are captured in the autophagosome and degraded in the lysosome. Autophagy plays two major roles: nutrient recycling under starvation or stress conditions and maintenance of cellular homeostasis by removing the damaged organelles or protein aggregates. In established cancer cells, autophagy-mediated nutrient recycling promotes tumor progression, whereas in normal/premalignant cells, autophagy suppresses tumor initiation by eliminating the oncogenic/harmful molecules. Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is refractory to most currently available treatment modalities, including immune checkpoint blockade and molecular-targeted therapy. One prominent feature of PDAC is its constitutively active and elevated autophagy-lysosome function, which enables PDAC to thrive in its nutrient-scarce tumor microenvironment. In addition to metabolic support, autophagy promotes PDAC progression in a metabolism-independent manner by conferring resistance to therapeutic treatment or facilitating immune evasion. Besides to cell-autonomous autophagy in cancer cells, host autophagy (autophagy in non-cancer cells) supports PDAC progression, further highlighting autophagy as a promising therapeutic target in PDAC. Based on a growing list of compelling preclinical evidence, there are numerous ongoing clinical trials targeting the autophagy-lysosome pathway in PDAC. Given the multifaceted and context-dependent roles of autophagy in both cancer cells and normal host cells, a deeper understanding of the mechanisms underlying the tumor-promoting roles of autophagy as well as of the consequences of autophagy inhibition is necessary for the development of autophagy inhibition-based therapies against PDAC.
    Keywords:  Anti-tumor immunity; Autophagy; Host autophagy; Lysosome; PDAC
    DOI:  https://doi.org/10.1007/s00535-022-01889-1
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