Journal Article

Reprogramming tumour-associated macrophages to outcompete cancer cells

Shi, Wei, Chou, Chun, Xu, Ke, Wang, Xinxin, Schmidt, Laura S., Do, Mytrang H., Ji, Liangliang, Li, Ming O., Ballabio, Andrea, Zhang, Xian, Zhang, Jing, Li, Shun, Capistrano, Kristelle J., Hsu, Ting-Wei, Malik, Isha, Linehan, W. Marston, Nixon, Briana G.

2023

Overview

In metazoan organisms, cell competition acts as a quality control mechanism to eliminate unfit cells in favour of their more robust neighbours 1 , 2 . This mechanism has the potential to be maladapted, promoting the selection of aggressive cancer cells 3 – 6 . Tumours are metabolically active and are populated by stroma cells 7 , 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 TFE3 9 – 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. In a mouse model of breast cancer, a low-protein diet induces engulfment activities and mTORC1 signalling in tumour-associated macrophages to suppress engulfment-dependent mTORC1 signalling in MYC-overexpressing cancer cells through cell competition, serving as an innate immune defence mechanism to slow tumour growth.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/2 / 13/31 / 13/51 / 13/95 / 38/35 / 38/91 / 631/250/2504/342/1726 / 631/250/580 / 64/60 / Amino acids / Amino Acids - metabolism / Animals / Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism / Breast cancer / Cancer therapies / Cell Competition - genetics / Cell Competition - immunology / Cellular Reprogramming Techniques / Competition / Deceleration / Depletion / Diet / Dietary Proteins - pharmacology / Disease Models, Animal / Environmental factors / Genotype & phenotype / GTP Phosphohydrolases - metabolism / Guanosine triphosphatases / Humanities and Social Sciences / Immunity, Innate / Low protein diet / Lysosomes - metabolism / Macrophages / Mechanistic Target of Rapamycin Complex 1 - metabolism / Mice / multidisciplinary / Mutation / Myc protein / Neoplasms - genetics / Neoplasms - immunology / Neoplasms - metabolism / Neoplasms - pathology / Nutrient deficiency / Phosphorylation / Proteins / Proto-Oncogene Proteins c-myc - genetics / Proto-Oncogene Proteins c-myc - metabolism / Quality control / Science / Science (multidisciplinary) / Signal transduction / Stem cells / Stroma / Transcription activation / Transcription factors / Tumor-Associated Macrophages - immunology / Tumor-Associated Macrophages - metabolism / Tumors