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Midkine expression by stem-like tumor cells drives persistence to mTOR inhibition and an immune-suppressive microenvironment
- Source :
- Nature Communications. 13
- Publication Year :
- 2022
- Publisher :
- Springer Science and Business Media LLC, 2022.
-
Abstract
- mTORC1 is hyperactive in multiple cancer types1,2. Here, we performed integrative analysis of single cell transcriptomic profiling, paired T cell receptor (TCR) sequencing, and spatial transcriptomic profiling on Tuberous Sclerosis Complex (TSC) associated tumors with mTORC1 hyperactivity, and identified a stem-like tumor cell state (SLS) linked to T cell dysfunction via tumor-modulated immunosuppressive macrophages. Rapamycin and its derivatives (rapalogs) are the primary treatments for TSC tumors, and the stem-like tumor cells showed rapamycin resistance in vitro, reminiscent of the cytostatic effects of these drugs in patients. The pro-angiogenic factor midkine (MDK) was highly expressed by the SLS population, and associated with enrichment of endothelial cells in SLS-dominant samples. Inhibition of MDK showed synergistic benefit with rapamycin in reducing the growth of TSC cell lines in vitro and in vivo. In aggregate, this study suggests an autocrine rapamycin resistance mechanism and a paracrine tumor survival mechanism via immune suppression adopted by the stem-like state tumor cells with mTORC1 hyperactivity.
- Subjects :
- Sirolimus
Multidisciplinary
TOR Serine-Threonine Kinases
Tumor Suppressor Proteins
Midkine
Endothelial Cells
General Physics and Astronomy
General Chemistry
Mechanistic Target of Rapamycin Complex 1
General Biochemistry, Genetics and Molecular Biology
Neoplasms
Tuberous Sclerosis Complex 2 Protein
Neoplastic Stem Cells
Tumor Microenvironment
Humans
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....2141e9078728870f3c05740dc138cd34