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Pieter Cory, BS




Research Staff


Brigham and Women's Hospital




Pieter Cory, Dean M. Rosenthal, Damir Khabibullin, Michel Alchoueiry, Mayuri Patel, William Gibbons, Heng-Jia Liu, Yan Tang, Volkhard Lindner, Nicola Alesi Elizabeth P. Henske

Principal Investigator


The Role of CTHRC1 in the Pathogenesis of LAM


Lymphangioleiomyomatosis (LAM) is a cystic lung disease which primarily affects women of childbearing age, with rapid progression during pregnancy. LAM is a manifestation of tuberous sclerosis complex (TSC), a hereditary disease caused by mutational inactivation of the TSC1 or TSC2 tumor suppressor genes.

Collagen triple helix repeat containing 1 (CTHRC1) is a secreted protein that is highly expressed in many cancers and associated with poor prognosis. CTHRC1 is implicated in tumor cell proliferation and invasion in several cancers.

We discovered a 10-fold increase of CTHRC1 expression in LAM patient-derived angiomyolipoma tissue compared to controls (p<0.0001). CTHRC1 is also elevated in cellular models of TSC, including Tsc1 and Tsc2-deficient mouse embryonic fibroblast (MEFs), and TSC2-deficient LAM patient-derived cells, relative to controls (~6-60-fold, p<.05). Furthermore, Cthrc1 mRNA is elevated ~250 fold (P < 0.0001) in kidney tissue from a ROSACreERT2 TSC2 mouse model. Cthrc1 knockdown decreases proliferation (~2.5-fold, P < 0.0001) and colony formation (~7-fold, P < 0.0001) in Tsc2-null cells, with no effect on TSC2-expressing cells. Transcription factors EB and E3 (TFEB/TFE3) are master coordinators of lysosomal biogenesis and autophagy; their transcriptional activity is hyperactivated in LAM. TFEB/TFE3 recognize a promoter sequence termed the CLEAR motif. CTHRC1 contains six CLEAR motifs upstream of its transcriptional start site. Importantly, CTHRC1 mRNA and protein expression are decreased by TFE3 knockdown in Tsc1 and Tsc2-null MEFs (~2-fold, p < 0.0001) and by TFEB knockdown in 621-102 cells (~2.5-fold, p < 0.01). Taken together, our results indicate CTHRC1 is upregulated in LAM via increased TFEB and TFE3 transcriptional activity; establishing for the first time that CTHRC1 is a TFEB/TFE3 target, and that CTHRC1 promotes cell proliferation.

Research Context

Lymphangioleiomyomatosis (LAM) is a destructive lung disease that mainly effects women of child-bearing age. There are two types of LAM, one which manifests in women who inherit a genetic disease called Tuberous Sclerosis Complex (TSC), and another which occurs spontaneously due to genetic mutation. It is predicted three to seven women per one million will have LAM. Unfortunately, many women with LAM are misdiagnosed with more prevalent lung diseases. LAM is a progressive disease that worsens over time. Symptoms include shortness of breath and chest pain, which may worsen to chronic coughing and wheezing. The cystic lung destruction progresses to lung collapse, pleural effusions, and premature death. Although many breakthroughs have occurred in LAM, the reasons for its striking female prevalence (>99% of cases are women) are poorly understood. This work aims to further develop mechanisms for LAM disease progression and to develop novel treatment and therapy options.