Loss of Tuberous Sclerosis Complex 2 confers inflammation via dysregulation of Nuclear factor kappa-light-chain-enhancer of activated B cells

TL;DR

This study shows that loss of TSC2 leads to inflammation via NF-κB and suggests combining NF-κB inhibitors with mTOR inhibitors could improve TSC treatment.

Contribution

The study identifies NF-κB-driven autocrine signaling in TSC2-deficient cells and proposes NF-κB inhibition as a novel therapeutic strategy.

Findings

NF-κB-regulated genes are enriched in TSC patient tumors and cell models.

TSC2 deficiency causes NF-κB and STAT3 activation through IL-6 autocrine signaling.

Combined mTORC1 and NF-κB inhibition prevents anchorage-independent growth and colony regrowth in TSC2-deficient cells.

Abstract

Aberrant activation of mTORC1 is clearly defined in TSC, causing uncontrolled cell growth. While mTORC1 inhibitors show efficacy to stabilise tumour growth in TSC, they are not fully curative. Disease facets of TSC that are not restored with mTOR inhibitors might involve NF-κB. The study aimed to characterise NF-κB in the context of TSC.

Enrichment of NF-κB-regulated genes was observed in TSC patient tumours, SEN/SEGAs, cortical tubers and a TSC tumour-derived cell line (621 – 101). Highlighting an inflammatory component of TSC, TSC cell models showed an elevated level of NF-κB and STAT3 activation. Herein, we report a dysregulated inflammatory phenotype of TSC2-deficient cells where NF-κB promotes autocrine signalling involving IL-6. Of importance, mTORC1 inhibition does not block this inflammatory signal to promote STAT3, while NF-κB inhibition was much more effective. Combined mTORC1 and NF-κB inhibition was potent at preventing anchorage-independent growth of TSC2-deficient cells, and unlike mTORC1 inhibition alone was sufficient to prevent colony regrowth after cessation of treatment.

This study reveals autocrine signalling crosstalk between NF-κB and STAT3 in TSC cell models. Furthermore, the data presented indicate that NF-κB pathway inhibitors could be a viable adjunct therapy with the current mTOR inhibitors to treat TSC.

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