mapping-metabolism-monitoring-lactate-dehydrogenase-activity-directly

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 ...

UCLA

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. We deleted Hmga2 in two mouse models of squamous cell carcinoma and found this gene to be dispensable. In fact, EMT, tumor initiation and progression all appeared to be mostly unaffected by the absence of Hmga2. Tumors lacking the ability to induce Hmga2 proceeded to initiate cutaneous spindle cell and squamous cell carcinomas with all the typical pathological and molecular hallmarks of these cancers.

Hmga2 is dispensable for cutaneous squamous cell carcinoma.

Tumor suppressor identity can contribute to heterogeneity of phenotype in hair follicle stem cell-induced 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. Here we provide a summary of data from our lab and others that demonstrate the ability of hair follicle stem cells to serve as cancer cells of origin, and the ability of various molecular players to drive heterogeneity of tumor cell types. A synthesis of these studies potentially could provide unique insights into the process by which Ras can initiate squamous cell carcinoma in human patients and could eventually inform treatment strategies.

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

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. Furthermore, lactate generation appears to be critical for the activation of HFSCs as deletion of lactate dehydrogenase (Ldha) prevented their activation. Conversely, genetically promoting lactate production in HFSCs through mitochondrial pyruvate carrier 1 (Mpc1) deletion accelerated their activation and the hair cycle. Finally, we identify small molecules that increase lactate production by stimulating Myc levels or inhibiting Mpc1 carrier activity and can topically induce the hair cycle. These data suggest that HFSCs maintain a metabolic state that allows them to remain dormant and yet quickly respond to appropriate proliferative stimuli.

Article	Year
Hmga2 is dispensable for cutaneous squamous cell carcinoma. Experimental dermatology\| PubMed ID: 26901496	2016
Tumor suppressor identity can contribute to heterogeneity of phenotype in hair follicle stem cell-induced squamous cell carcinoma. Experimental dermatology\| PubMed ID: 27095696	2016
Exploiting Mouse Models to Study Ras-Induced Cutaneous Squamous Cell Carcinoma. The Journal of investigative dermatology\| PubMed ID: 27160068	2016
Lactate dehydrogenase activity drives hair follicle stem cell activation. Nature cell biology\| PubMed ID: 28812580	2017

Aimee Flores

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