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Inactivation of mTORC2 in macrophages is a signature of colorectal cancer that promotes tumorigenesis

Katholnig, Karl, Schütz, Birgit, Fritsch, Stephanie D., Schörghofer, David, Linke, Monika, Sukhbaatar, Nyamdelger, Matschinger, Julia M., Unterleuthner, Daniela, Hirtl, Martin, Lang, Michaela, Herac, Merima, Spittler, Andreas, Bergthaler, Andreas, Schabbauer, Gernot, Bergmann, Michael, Dolznig, Helmut, Hengstschläger, Markus, Magnuson, Mark A., Mikula, Mario, Weichhart, Thomas·2019·JCI Insight
DOI 10.1172/jci.insight.124164
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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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Metadata

Authors
Katholnig, K., Schütz, B., Fritsch, S. D., Schörghofer, D., Linke, M., Sukhbaatar, N., Matschinger, J. M., Unterleuthner, D., Hirtl, M., Lang, M., Herac, M., Spittler, A., Bergthaler, A., Schabbauer, G., Bergmann, M., Dolznig, H., Hengstschläger, M., Magnuson, M. A., Mikula, M., & Weichhart, T.
Affiliations
  • Center of Pathobiochemistry and Genetics, Institute of Medical Genetics,
  • Department of Internal Medicine III, Division of Gastroenterology and Hepatology,
  • Clinical Institute of Pathology, and
  • Core Facility Flow Cytometry & Surgical Research Laboratories, Medical University of Vienna, Vienna, Austria.
  • CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria.
  • Institute for Physiology, Center for Physiology and Pharmacology, and
  • Division of General Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.
  • Department of Molecular Physiology and Biophysics and Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
ORCID
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2019-10-17
Volume
4
Issue
20
ISSN
2379-3708
DOI
10.1172/jci.insight.124164
Cited by
29
References
2
Language
en
Funders
  • FWF (P30857-B28,P27701-B20, P25336-B13)
  • WWTF (LS18-058)

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