Reprogramming tumour-associated macrophages to outcompete cancer cells Journal Article


Authors: Zhang, X.; Li, S.; Malik, I.; Do, M. H.; Ji, L.; Chou, C.; Shi, W.; Capistrano, K. J.; Zhang, J.; Hsu, T. W.; Nixon, B. G.; Xu, K.; Wang, X.; Ballabio, A.; Schmidt, L. S.; Linehan, W. M.; Li, M. O.
Article Title: Reprogramming tumour-associated macrophages to outcompete cancer cells
Abstract: In metazoan organisms, cell competition acts as a quality control mechanism to eliminate unfit cells in favour of their more robust neighbours1,2. This mechanism has the potential to be maladapted, promoting the selection of aggressive cancer cells3–6. Tumours are metabolically active and are populated by stroma cells7,8, but how environmental factors affect cancer cell competition remains largely unknown. Here we show that tumour-associated macrophages (TAMs) can be dietarily or genetically reprogrammed to outcompete MYC-overexpressing cancer cells. In a mouse model of breast cancer, MYC overexpression resulted in an mTORC1-dependent ‘winner’ cancer cell state. A low-protein diet inhibited mTORC1 signalling in cancer cells and reduced tumour growth, owing unexpectedly to activation of the transcription factors TFEB and TFE3 and mTORC1 in TAMs. Diet-derived cytosolic amino acids are sensed by Rag GTPases through the GTPase-activating proteins GATOR1 and FLCN to control Rag GTPase effectors including TFEB and TFE39–14. Depletion of GATOR1 in TAMs suppressed the activation of TFEB, TFE3 and mTORC1 under the low-protein diet condition, causing accelerated tumour growth; conversely, depletion of FLCN or Rag GTPases in TAMs activated TFEB, TFE3 and mTORC1 under the normal protein diet condition, causing decelerated tumour growth. Furthermore, mTORC1 hyperactivation in TAMs and cancer cells and their competitive fitness were dependent on the endolysosomal engulfment regulator PIKfyve. Thus, noncanonical engulfment-mediated Rag GTPase-independent mTORC1 signalling in TAMs controls competition between TAMs and cancer cells, which defines a novel innate immune tumour suppression pathway that could be targeted for cancer therapy. © 2023, The Author(s), under exclusive licence to Springer Nature Limited.
Keywords: signal transduction; controlled study; protein expression; unclassified drug; genetics; nonhuman; neoplasm; neoplasms; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; gene overexpression; breast cancer; transcription initiation; animal experiment; animal model; protein; cohort analysis; transcription factor; cancer therapy; cancer inhibition; myc protein; cancer cell; guanosine triphosphatase activating protein; amino acid; tumor growth; tumor; oncogene myc; lysosome; gtp phosphohydrolases; lysosomes; growth inhibition; mouse model; basic helix loop helix leucine zipper transcription factor; basic helix-loop-helix leucine zipper transcription factors; guanosine triphosphatase; protein restriction; tumor-associated macrophage; mammalian target of rapamycin complex 1; tumor-associated macrophages; metazoan; cell component; transcription factor e3; cancer; female; article; cell competition; protein diet; mechanistic target of rapamycin complex 1; gator 1 protein; transcription factor eb
Journal Title: Nature
Volume: 619
Issue: 7970
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2023-07-20
Start Page: 616
End Page: 623
Language: English
DOI: 10.1038/s41586-023-06256-5
PUBMED: 37380769
PROVIDER: scopus
PMCID: PMC10719927
DOI/URL:
Notes: Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Ming Li -- Source: Scopus
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MSK Authors
  1. Ming Li
    111 Li
  2. Ke   Xu
    11 Xu
  3. Wei   Shi
    11 Shi
  4. Mytrang   Do
    16 Do
  5. Briana Glyn Nixon
    24 Nixon
  6. Chun Chou
    12 Chou
  7. Shun Li
    7 Li
  8. Xian Zhang
    12 Zhang
  9. Xinxin Wang
    6 Wang
  10. Ting-Wei Hsu
    3 Hsu
  11. Jing Zhang
    5 Zhang
  12. Liangliang Ji
    6 Ji
  13. Isha Malik
    1 Malik