Mesenchymal Tumorigenesis Driven by TSC2 Haploinsufficiency Requires HMGA2 and Is Independent of mTOR Pathway Activation

Abstract

Tuberous sclerosis (TSC) is a tumor suppressor gene syndrome that is associated with the widespread development of mesenchymal tumor types. Genetically, TSC is said to occur through a classical bi-allelic inactivation of either TSC genes (TSC1, hamartin or TSC2, tuberin), an event that is implicated in the induction of the mTOR pathway and subsequent tumorigenesis. High Mobility Group A2 (HMGA2), an architectural transcription factor, is known to regulate mesenchymal differentiation and drive mesenchymal tumorigenesis in vivo. Here, we investigated the role of HMGA2 in the pathogenesis of TSC using the TSC2+/- mouse model that similarly mirrors human disease and human tumor samples. We show that HMGA2 expression was detected in 100% of human and mouse TSC tumors, and that HMGA2 activation was required for TSC mesenchymal tumorigenesis in genetically engineered mouse models. In contrast to the current dogma, the mTOR pathway was not activated in all TSC2+/- tumors and was elevated in only 50% of human mesenchymal tumors. Moreover, except for a subset of kidney tumors, tuberin was expressed in both human and mouse tumors. Therefore, haploinsufficiency of one TSC tumor suppressor gene was required for tumor initiation, but further tumorigenesis did not require the second hit, as previously postulated. Collectively, these findings demonstrate that tissue-specific genetic mechanisms are employed to promote tumor pathogenesis in TSC, and identify a novel, critical pathway for potential therapeutic targeting.

Human Pluripotent Stem Cell–Derived TSC2-Haploinsufficient Smooth Muscle Cells Recapitulate Features of Lymphangioleiomyomatosis

“…Thus, it is possible that TSC2 +/− cells may potentiate disease phenotypes within LAM nodules. Our observations align with recent studies showing that TSC2 +/− cells can exhibit some disease-associated phenotypes and may contribute to pathology in TSC and LAM (20–23), and that TSC2 -expressing cells can acquire aberrant phenotypes when associated with TSC2 -deficient cells (49). It is important to note, however, that while some phenotypes were unchanged ( e.g.…”

“…Given a potential pathogenic role for TSC2 +/− cells in TSC and LAM lesions(20–23), we focused on two tumor-derived (P6T1, P6T2) and two normal-appearing dermal-derived (P6N1, P6N2) P6 TSC2 +/− iPSC lines. Overall, these cell lines demonstrate elevated mTORC1 signaling, evidenced by increased phosphorylation of S6 kinase (P-S6K) compared to WT non-patient iPSC controls (969B and 168) (Fig.…”

Tuberous Sclerosis Complex Associated with Vascular Anomalies or Overgrowth

“…A recent case report highlighted that lymphedema is a possible complication of mTOR inhibition, especially in young individuals . As described above, another recent publication has demonstrated that mTOR overactivity is not ubiquitous in many TSC‐related tumors in a murine model and in the setting of a TSC2 genotype . Lastly, perhaps the number of cases here was too small to detect any beneficial effect that mTOR inhibition may have on a larger, more narrowly defined cohort.…”

Lung function response and side effects to rapamycin for lymphangioleiomyomatosis: a prospective national cohort study

“…Importantly, this favourable lung function response was not simply accounted for by higher rapamycin levels in this group. It is possible that those with the least response to rapamycin have disease that is less dependent on mTOR dysregulation as suggested by the finding that signalling pathways other than mTOR contribute to tumourigenesis in LAM cells 20. In addition, VEGF-D is synthesised by LAM cells and is a transcriptional target of mTOR: the finding that higher levels of serum VEGF-D are associated with a better response to rapamycin is potentially consistent with differing levels of mTOR dysregulation and influence on the disease phenotype between individuals 21.…”