Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition.

A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine-limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo, genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggest that PHGDH inhibitors may be useful in the treatment of brain metastasis. SIGNIFICANCE: Using proteomics, metabolomics, and multiple brain metastasis models, we demonstrate that the nutrient-limited environment of the brain potentiates brain metastasis susceptibility to serine synthesis inhibition. These findings underscore the importance of studying cancer metabolism in physiologically relevant contexts, and provide a rationale for using PHGDH inhibitors to treat brain metastasis.This article is highlighted in the In This Issue feature, p. 1241.

Skills in Open Surgery do not Predict Arthroscopic Skills in Medical Students.

OBJECTIVE: Teaching of basic open surgical skills like skin closure has been well established in medical schools' surgical curricula. The same cannot be said for basic arthroscopic skills even though the importance of arthroscopic surgery in Orthopaedics has been well documented. The goal of this study was to evaluate the relationship between basic skills in open surgery and basic arthroscopic skills in a cohort of medical students. Our hypothesis was that performance in open surgical skills does not correlate with skills in arthroscopic surgery. DESIGN: The performance of medical students in basic tasks in open surgery (porcine model: subcutaneous and skin suturing) and arthroscopic surgery (bench top model: arthroscopic triangulation and object transfer) was assessed. For both surgical techniques an introductory course was given followed by a standardized assessment. After 1 week both open and arthroscopic tasks were reassessed. All procedures were recorded and scored by 2 independent observers in a blinded fashion. SETTING: The study was performed at the skills lab of the Clinic for Orthopaedics and Tumororthopaedics at University Hospital Muenster in Muenster Germany. PARTICIPANTS: A cohort of 21 medical students (average age 22.2 years) participated in this study. The cohort consisted of 17 female (81%) and 4 male (19%) students. All students were in the clinical part of their study and had not received any prior surgical education. RESULTS: Interobserver reliability was very high for the arthroscopic tasks and high for the open surgery tasks. No correlation was found between open and arthroscopic skills. For the first assessment the correlation coefficient was r = 0.197 (p = 0.391). For the second assessment the correlation coefficient was r = 0.212 (p = 0.356). Significant improvement from first to second assessment was only found for the arthroscopic tasks (p < 0.0001) while improvement in the open surgery performance failed to reach statistical significance (p = 0.184). CONCLUSIONS: The results of this study suggest that performance in open surgical skills does not correlate with performance in arthroscopic skills and should be taught independent from each other. Arthroscopic skills can effectively be taught with bench top training systems in a time- and resource efficient manner, with measurable results even in a 1-day-course setup. Arthroscopic skills training may be offered in undergraduate curricula in addition to open surgical skills training to students with an interest in Orthopaedics.