Role of the Secreted Factor CTHRC1 in the Pathogenesis of TSC
Abstract
This project is focused on a protein, CTHRC1 (collagen triple-helix repeat containing 1), that has never before been studied in tuberous sclerosis complex (TSC). In other diseases, CTHRC1 is linked to the rate of cellular growth, and in several types of cancer, a high level of CTHRC1 is associated with a poor clinical prognosis. In a new line of investigation in our lab, we have discovered that levels of CTHRC1 are strikingly elevated in cells that lack the TSC proteins. At the messenger RNA level, CTHRC1 is elevated 15-fold in TSC1-deficient cells vs. controls, and in TSC2-deficient cells CTHRC1 is elevated 100-fold. These levels of elevation are remarkable – very few TSC-associated genes show levels of elevation in this range. Interestingly, in cells, these high levels of CTHRC1 are not suppressed by Rapamycin. Levels of CTHRC1 are also increased in human angiomyolipomas and in lymphangioleiomyomatosis (LAM) cells. In TSC2-deficient cells, CTHRC1 is a major determinant of cellular growth. If we inhibit CTHRC1, the growth of the cells decreases about 2.5-fold in the conventional growth system (on plastic dishes) and decreases about 5-fold in a three-dimensional assay called colony formation. These data suggest that CTHRC1 is a newly recognized and important driver of tumor cell growth in TSC. Because it is not affected by the mTOR inhibitor Rapamycin (which is similar to everolimus/Afinitor), CTHRC1 could help to explain why tumors in TSC are not eliminated during therapy with mTOR inhibitors. The critical next step, and a major part of this proposal, is to test the importance of CTHRC1 in mouse models of TSC. If CTHRC1 promotes the growth of tumors in TSC, this could pave the way to a completely new concept for treatment, perhaps combining drugs or antibodies that target CTHRC1 with mTORC1 inhibitors. This could also help us understand the fundamental reasons why mTORC1 inhibitors do not eliminate tumor cells in TSC. Identifying therapeutic strategies to eliminate tumor cells in TSC, a key goal of this work, is a critical step toward a cure for TSC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310215
Entities
People
- Nicola Alesi
Organizations
- United States Army