ArticleJCI insight2019
Inactivation of mTORC2 in macrophages is a signature of colorectal cancer that promotes tumorigenesis.
Article in JCI insight, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 25 citations in OpenAlex.
- The role of mTORC2/RICTOR in immune cells and inflammatory diseases.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- Review
- Single-Cell RNA-Seq Combined With Bulk RNA-Seq Revealed the Involvement of Pancreatic Cancer Tissue-Resident Macrophages in Tumour Progression and the Immunotherapy Response.Journal of cellular and molecular medicine · 2026Article
- The role of tumor-associated macrophages in cancer development and their significance as prognostic markers.Clinical and experimental medicine · 2026Review
- mTOR in radiotherapy of lung cancer: Mechanisms of radiation resistance and therapeutic implications (Review).International journal of oncology · 2026Review
- Macrophage polarization in ischemia-reperfusion injury: from molecular mechanisms to therapeutic strategies.Frontiers in immunology · 2026Review
- mTORC2 inhibition reduces tumor burden via STAT1 activation and enhanced response to anti-PD-L1 therapy.Cell death & disease · 2025Article
- mTOR Signaling in Macrophages: All Depends on the Context.International journal of molecular sciences · 2025Review
- Tissue-Resident Macrophages in Cancer: Friend or Foe?Cancer medicine · 2024Review
- Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer.World journal of gastrointestinal oncology · 2024Review
- SIX4 Activation in Inflammatory Response Drives the Transformation of Colorectal Epithelium into Inflammation and Tumor via Feedback-Enhancing Inflammatory Signaling to Induce Tumor Stemness Signaling.International journal of biological sciences · 2024Article
- Colitis-associated carcinogenesis: crosstalk between tumors, immune cells and gut microbiota.Cell & bioscience · 2023Review
- Role of glycolysis in inflammatory bowel disease and its associated colorectal cancer.Frontiers in endocrinology · 2023Review
- A pan-cancer analysis of the oncogenic role of secreted phosphoprotein 1 (SPP1) in human cancers.Annals of translational medicine · 2022Article
- Review
- Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry.Nature communications · 2021Article
- Dual blockade of EGFR and CDK4/6 delays head and neck squamous cell carcinoma progression by inducing metabolic rewiring.Cancer letters · 2021Article
- Clinical Potential of Kinase Inhibitors in Combination with Immune Checkpoint Inhibitors for the Treatment of Solid Tumors.International journal of molecular sciences · 2021Review
- Osteopontin Blockade Immunotherapy Increases Cytotoxic T Lymphocyte Lytic Activity and Suppresses Colon Tumor Progression.Cancers · 2021Article
- Recent Advances in Our Knowledge of mCRC Tumor Biology and Genetics: A Focus on Targeted Therapy Development.OncoTargets and therapy · 2021Review
Corrections and comments
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Authors and funding
20 authors at 6 institutions in 4 countries.
Funding
Abstract
The mechanistic target of rapamycin complex 2 (mTORC2) is a potentially novel and promising anticancer target due to its critical roles in proliferation, apoptosis, and metabolic reprogramming of cancer cells. However, the activity and function of mTORC2 in distinct cells within malignant tissue in vivo is insufficiently explored. Surprisingly, in primary human and mouse colorectal cancer (CRC) samples, mTORC2 signaling could not be detected in tumor cells. In contrast, only macrophages in tumor-adjacent areas showed mTORC2 activity, which was downregulated in stromal macrophages residing within human and mouse tumor tissues. Functionally, inhibition of mTORC2 by specific deletion of Rictor in macrophages stimulated tumorigenesis in a colitis-associated CRC mouse model. This phenotype was driven by a proinflammatory reprogramming of mTORC2-deficient macrophages that promoted colitis via the cytokine SPP1/osteopontin to stimulate tumor growth. In human CRC patients, high SPP1 levels and low mTORC2 activity in tumor-associated macrophages correlated with a worsened clinical prognosis. Treatment of mice with a second-generation mTOR inhibitor that inhibits mTORC2 and mTORC1 exacerbated experimental colorectal tumorigenesis in vivo. In conclusion, mTORC2 activity is confined to macrophages in CRC and limits tumorigenesis. These results suggest activation but not inhibition of mTORC2 as a therapeutic strategy for colitis-associated CRC.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.