Research Assistant II
Pulmonary and Critical Care Medicine
Dean M. Rosenthal, Nicola Alesi, Damir Khabibullin, Pieter M. Cory, Jennifer A. Chen, Michel Alchoueiry, Heng-Jia Liu, Yan Tang, Eli Akl, Julia F. Charles, Volkhard Lindner, Elizabeth P. Henske
Research Category: Cancer
Tuberous Sclerosis Complex (TSC) is a hereditary cancer syndrome caused by mutational inactivation of TSC1 or TSC2 tumor suppressor genes, resulting in hyperactivation of the kinase mTORC1.
CTHRC1 (Collagen Triple Helix Repeat Containing Protein 1) is a secreted protein that is highly expressed in many cancers, where it is associated with disease progression.
We have found that Cthrc1 mRNA expression is elevated ~5-fold in TSC-associated angiomyolipoma relative to normal kidney tissue, and ~250 fold in kidney tissue from an unpublished TSC mouse model.
Cthrc1 mRNA is elevated 15 to 60-fold in Tsc1-/- MEFs, Tsc2-/- MEFs, and TSC2-deficient angiomyolipoma-derived 621 cells, relative to controls. Cthrc1 knockdown decreased proliferation (~40%, P < 0.0001) and colony formation (~70%, P < 0.0001) of Tsc2-/- MEFs with no effect on Tsc2+/+ MEFs. Rapamycin (mTORC1 inhibitor with partial clinical efficacy on TSC lesions) does not decrease CTHRC1 expression in these cell lines.
However, Cthrc1 expression is decreased by TFEB/TFE3 knockdown in Tsc1-/- MEFs (~50%, p < 0.0001) and 621 cells (~60%, p < 0.01). TFEB and TFE3 are transcription factors previously recognized to be hyperactive in TSC. These results indicate that in TSC-deficient cells, CTHRC1 expression is elevated and dependent on TFEB/TFE3 hyperactivation.
Tuberous Sclerosis Complex (TSC) is a hereditary cancer caused by mutational inactivation of TSC1 or TSC2 tumor suppressor genes, resulting in hyperactivation of a protein called mTORC1.
This project is focused on another protein, CTHRC1, that has never been studied in TSC. CTHRC1 is linked to the rate of cellular growth in other diseases, where it is associated with poor prognosis.
We have discovered that CTHRC1 levels are strikingly elevated in cells that lack the TSC proteins. CTHRC1 is elevated 15-fold in TSC1-deficient cells vs. controls, and in TSC2-deficient cells, CTHRC1 is elevated 60-fold. These high levels of CTHRC1 are not suppressed by the mTORC1 inhibitor Rapamycin (used in TSC clinic). Levels of CTHRC1 are also increased in human angiomyolipomas (a TSC-associated kidney tumor) and in kidneys from mice with TSC.
In TSC2-deficient cells, CTHRC1 is a determinant of cellular growth. If we inhibit CTHRC1, the growth decreases ~2.5-fold on plastic dishes and ~3.5-fold in a colony formation assay.
These data suggest that CTHRC1 is an important driver of tumor cell development in TSC. Because CTHRC1 expression is not affected by the Rapamycin, the protein could help explain why tumors in TSC are not eliminated by therapy with mTORC1 inhibitors.