Midkine expression by stem-like tumor cells drives persistence to mTOR inhibition and an immune-suppressive microenvironment.

ABSTRACT: mTORC1 is hyperactive in multiple cancer types^1,2. 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-dominan

SUBMITTER: Tang Y 

PROVIDER: S-EPMC9418323 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature