Defining metabolic flexibility in hair follicle stem cell induced squamous cell carcinoma.

We previously showed that inhibition of glycolysis in cutaneous squamous cell carcinoma (SCC)-initiating cells had no effect on tumorigenesis, despite the perceived requirement of the Warburg effect, which was thought to drive carcinogenesis. Instead, these SCCs were metabolically flexible and sustained growth through glutaminolysis, another metabolic process frequently implicated to fuel tumorigenesis in various cancers. Here, we focused on glutaminolysis and genetically blocked this process through glutaminase (GLS) deletion in SCC cells of origin.

Inhibition of pyruvate oxidation as a versatile stimulator of the hair cycle in models of alopecia.

Hair follicle stem cells (HFSCs) are known to be responsible for the initiation of a new hair cycle, but typically remain quiescent for very long periods. In alopecia, or hair loss disorders, follicles can be refractory to activation for years or even permanently. Alopecia can be triggered by autoimmunity, age, chemotherapeutic treatment, stress, disrupted circadian rhythm or other environmental insults.

Development of Novel Mitochondrial Pyruvate Carrier Inhibitors to Treat Hair Loss.

Herein, we report the synthesis and evaluation of novel analogues of UK-5099 both and for the development of mitochondrial pyruvate carrier (MPC) inhibitors to treat hair loss. A comprehensive understanding of the structure-activity relationship was obtained by varying four positions of the hit compound, namely, the alkyl group on the N1 position, substituents on the indole core, various aromatic and heteroaromatic core structures, and various Michael acceptors. The major discovery was that the inhibitors with a 3,5-bis(trifluoromethyl)benzyl group at the N1 position were shown to have much better activity than (UK-5099) to increase cellular lactate production.

Extracellular Matrix Remodeling Regulates Glucose Metabolism through TXNIP Destabilization.

The metabolic state of a cell is influenced by cell-extrinsic factors, including nutrient availability and growth factor signaling. Here, we present extracellular matrix (ECM) remodeling as another fundamental node of cell-extrinsic metabolic regulation. Unbiased analysis of glycolytic drivers identified the hyaluronan-mediated motility receptor as being among the most highly correlated with glycolysis in cancer.

Mapping Metabolism: Monitoring Lactate Dehydrogenase Activity Directly in Tissue.

Mapping enzymatic activity in space and time is critical for understanding the molecular basis of cell behavior in normal tissue and disease. In situ metabolic activity assays can provide information about the spatial distribution of metabolic activity within a tissue. We provide here a detailed protocol for monitoring the activity of the enzyme lactate dehydrogenase directly in tissue samples.

Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism.

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation.

Lactate dehydrogenase activity drives hair follicle stem cell activation.

Although normally dormant, hair follicle stem cells (HFSCs) quickly become activated to divide during a new hair cycle. The quiescence of HFSCs is known to be regulated by a number of intrinsic and extrinsic mechanisms. Here we provide several lines of evidence to demonstrate that HFSCs utilize glycolytic metabolism and produce significantly more lactate than other cells in the epidermis.

Exploiting Mouse Models to Study Ras-Induced Cutaneous Squamous Cell Carcinoma.

Recently developed methods have allowed for the delivery of cancer-causing genetic mutations to particular cell types in the epidermis in an inducible fashion. These methods have allowed for sophisticated explorations on the cellular and molecular origins of squamous cell carcinoma due to oncogenic mutations in Ras. These experiments have provided insights into whether cancer is initiated by stem or more specified cells under various conditions, and have highlighted the ability of particular genetic hits to serve as tumor initiators or promoters.

Hmga2 is dispensable for cutaneous squamous cell carcinoma.

Hmga2 functions as a chromatin-associated factor during development, but is not expressed in most adult tissues. Expression of Hmga2 in adult tissues has been associated with a variety of human cancers. Numerous studies have implicated Hmga2 in epithelial-to-mesenchymal transition (EMT) and cancer progression through gain of function studies, but it is unclear whether Hgma2 is necessary for EMT, tumor formation or tumor progression.