- Our laboratory was the first to discover the physical interaction between the TSC1 and TSC2 proteins. Cancer Research, 1998
- We discovered that the sporadic form of LAM is caused by somatic TSC2 mutation PNAS, 2000
- Our lab first discovered that all three components of angiomyolipomas arise from a common precursor cell, American Journal of Pathology, 2003
- We found a distinctive abnormality of amino acid sensing in Tsc1 and Tsc2-deficient S. Pombe.
Journal of Biological Chemistry, 2004
- We discovered that the Notch signaling pathway is active in angiomyolipoma-derived cells and that the Notch pathway is activated in Drosophila models of TSC. Journal of Clinical Investigation, 2010
- Our lab discovered that autophagy and the autophagy substrate p62/Sequestosome1are critical to the in vivo growth of TSC2-null cells. PNAS, 2011
- We identified mTORC1 as a regulator of microRNA biogenesis. PLoS One, 2013
- Our high-throughput drug screen identified chelerythrine as a selective death inducer in TSC2-deficient cells, demonstrating hypersensitivity to oxidative stress-depending cell death. Molecular Cancer Research, 2015
- Through whole exome sequencing, we found that TSC2, and less commonly TSC1, alterations are the primary essential driver event in angiomyolipoma/LAM, and that somatic mutations rarely contribute to tumor development in this setting, PLoS Genetics, 2016
- Our lab performed the first metabolomic profiling of ChRCC, revealing an unexpected defect in the gamma-glutamyl cycle, and glutathione salvage pathway, with key therapeutic implications. PNAS, 2018
- We demonstrated the efficacy of checkpoint blockade in preclinical models of TSC and LAM. Journal of Clinical Investigation Insight, 2018
- We discovered that macropinocytosis is elevated in TSC2-deficient cells via a VPS34-dependent mechanism. Scientific Reports, 2018
Clinical features of TSC
Tuberous Sclerosis Complex (TSC) is a rare genetic disease, caused by mutational inactivation of either the TSC1or TSC2 tumor suppressor gene. TSC affects multiple organs including the brain, heart, kidney, lung and skin.
Genetics of TSC
Individuals with TSC have inactivating germline loss-of-function mutations in TSC1or TSC2. The TSC1 and TSC2 genes are tumor suppressor genes. Tumors, including renal angiomyolipomas, facial angiofibromas, and pulmonary lymphangioleiomyomatosis (LAM), develop after somatic “second hit” inactivation of the remaining wild-type allele of TSC1 or TSC2.
Biochemical Function of the TSC Proteins
The TSC protein complex integrates signals from the cellular environment, including growth factors and nutrients to regulate the activity of mechanistic/mammalian target of rapamycin complex 1 (mTORC1). mTORC1 controls numerous essential metabolic processes, including protein and lipid synthesis, glycolysis/ATP production, lysosome and mitochondrial biogenesis and autophagy
Current Treatment of TSC
Sirolimus (Rapamycin), an mTORC1 inhibitor, is FDA-approved for the treatment of LAM, and everolimus, which is similar to sirolimus and also inhibits mTORC1, is FDA-approved for the treatment of certain manifestations of TSC, including angiomyolipomas and subependymal giant cell astrocytomas. Sirolimus and everolimus are referred to as “Rapalogs.”
Why are new Treatments for TSC a Priority?
Rapalogs (sirolimus/Rapamycin and everolimus) partially shrink TSC tumors, but do not eliminate them. The tumors grow back when the drugs are stopped. Therefore, many individuals with TSC and LAM need lifelong therapy. This highlights the unmet clinical need for treatments that induce long term disease-free remissions.
Role of the Henske Lab in TSC Research
The Henske Lab has been dedicated to understanding the signaling pathways implicated in TSC and its many manifestations. In 1998, Dr. Henske was the first to report the physical interaction between the TSC1 and TSC2 proteins, which is fundamental to our understanding of TSC. Since then, her research has expanded into the role of autophagy, nutrient uptake, lysosomes, and miRNA in the pathogenesis of TSC. She is also committed to identifying cellular pathways and drugs that will lead to the elimination of tumors in individuals with TSC and a cure for TSC.
Features of ChRCC
Chromophobe renal cell carcinoma (ChRCC) accounts for ~5% of all sporadic renal cancers. ChRCC can occur in two autosomal dominant genetic syndromes: Birt-Hogg-Dube (BHD) syndrome and Tuberous Sclerosis Complex (TSC). They are distinguished from other forms of RCC in part because of their abundant, morphologically-abnormal mitochondria. A fundamental molecular feature of ChRCC is the recurrent pattern of multiple chromosomal losses, including chromosomes 1, 2, 6, 10, 13, and 17. While tremendous progress has been made in more common forms of RCC, including clear cell RCC, there are currently no specific therapies for ChRCC, and the prognosis for metastatic ChRCC is believed to be poorer than for clear cell RCC.
Genetics of ChRCC
Interestingly, the Cancer Genome Atlas (TCGA0 identified elevated expression of mitochondrial genes and mutations of mitochondrial DNA as characteristic features of ChRCC, and 18% of the tumors carry heteroplasmic mutations in the mitochondrial genes ND1 or ND5, suggesting that metabolic mechanisms may be critical in this disease.
Role of the Henske Lab in ChRCC Research
The goal of our lab is to determine the fundamental metabolic mechanisms contributing to chromophobe-RCC tumorigenesis and to develop a metabolically-targeted therapeutic strategy for individuals with recurrent or metastatic ChRCC, for whom there are currently no proven therapeutic options. Our lab performed the first metabolomic profiling of ChRCC, revealing an unexpected defect in the gamma-glutamyl cycle, with decreased levels of gamma-glutamyl amino acids. This defect is linked to the key enzyme of this pathway, gamma-glutamyl transferase 1 (GGT1), which is expressed at a ~100 fold lower level in ChRCC vs normal kidney in TCGA dataset. These data suggest that a defective glutathione salvage pathway might be “an Achilles’ heel” to ChRCC, leading to sensitization to oxidative stress, mitochondrial damage and programming of glutamine and glucose metabolism.
Clinical Features of BHD
BHD is associated with renal cell carcinoma, cystic lung disease, and facial fibrofolliculomas. Individuals with BHD have a 50 fold higher risk of pneumothorax compared to their health counterpart. BHD is caused by germline loss-of-function mutations in the folliculin (FLCN) gene on the short arm of chromosome 17.
Role of the Henske Lab in BHD Research
Our lab generated the first yeast model of BHD and the first heterozygous mouse model of BHD. We currently use folliculin null cells and mouse models to study BHD. Mice with one allele of FLCN do not have airspace enlargement, however, they tend to have worse lung injury upon ventilation at high tidal volumes, leading to the “stretch hypothesis.” This hypothesis proposes that BHD cysts arise due to defects in cell-cell adhesion, leading to stretch-induced stress, particularly in regions of the lung with larger changes in alveolar volume and at weaker “anchor points” to the pleura. This is supported by the finding that FLCN downregulation leads to increased cell-cell interaction. Our lab also identified the interaction between FLCN and plakophilin 4 (PKP4), indicating that FLCN plays a role in cell-cell adhesion.
Clinical Features of Angiomyolipomas
Three types of renal lesions occur in TSC: renal cell carcinomas (which is uncommon), renal cysts (which can resemble polycystic kidney disease), and angiomyolipomas, which are usually multiple and bilateral. Angiomyolipomas are composed of smooth muscle cells, thick-walled vessels and adipose tissue, causing pain and can spontaneously hemorrhage, with life-threatening consequences.
Current Treatment of TSC
Pivotal clinical trials have demonstrated that the mTORC1 inhibitors sirolimus (Rapamycin) and its analog, everolimus (Afinitor) decrease the size of angiomyolipomas in TSC, but the angiomyolipomas regrow when treatment is stopped. Therefore, continuous, life-long therapy appears to be required.
Role of the Henske Lab in Angiomyolipoma Research
Our research is focused on identifying therapeutic strategies to eliminate, rather than suppress, tumor cells in TSC. This is among the highest priorities in the TSC field, since it would decrease the need for continuous, lifelong therapy with Rapamycin or everolimus.
Clinical Features and Prevalence of LAM
LAM is an unusual lung disease in which benign-appearing smooth muscle cells proliferate extensively in the lungs, leading to cystic, emphysema-like lung destruction. For reasons that are not yet completely understood, LAM affects almost exclusively women. LAM progresses most rapidly in premenopausal women, and can lead to shortness of breath, lung collapse, oxygen dependency, and lung failure. LAM occurs in a sporadic form (sporadic LAM) and in women with TSC (TSC-LAM). Among women with sporadic LAM, about a third have renal angiomyolipomas. Histologically, angiomyolipomas and LAM appear identical between sporadic LAM and TSC.
Role of the Henske Lab in LAM Research
The Henske group is best known for discovering that sporadic LAM is caused by somatic TSC2 mutations. We also discovered (using genetic approaches) that when LAM recurs after lung transplantation, the source of the recurrent LAM is the patient’s original LAM cells. Based on these genetic data, we proposed the hypothesis that LAM cells metastasize to the lung, despite the fact that they are histologically benign, or the “benign metastasis” model. Recently, it has been proposed that LAM should be reclassified as a low-grade neoplasm.
Examples of Bench-to-bedside LAM Research Arising from Henske Lab Discoveries
As one example of bench-to-bedside translation in LAM, our discovery of TSC2 mutations as a cause of sporadic LAM led to a multicenter clinical trial demonstrating the efficacy of sirolimus in LAM. Another example is the Sirolimus and Autophagy Inhibition in LAM (SAIL) trial, which tested the safety of hydroxychloroquine and sirolimus and LAM, based on data from the Henske Lab.