Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D as a regulator of tumor cell transmigration through the blood–brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis. Significance: Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that ex vivo–cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain. This article is highlighted in the In This Issue feature, p. 1

OBJECTIVE: Excessive dissatisfaction and stress among physicians can precipitate burnout, which results in diminished productivity, quality of care, and patient satisfaction and treatment adherence. Given the multiplicity of its harms and detriments to workforce retention and in light of the growing physician shortage, burnout has garnered much attention in recent years. Using a national survey, the authors formally evaluated burnout among neurosurgery trainees.METHODS: An 86-item questionnaire was disseminated to residents in the American Association of Neurological Surgeons database between June and November 2015. Questions evaluated personal and workplace stressors, mentorship, career satisfaction, and burnout. Burnout was assessed using the previously validated Maslach Burnout Inventory. Factors associated with burnout were determined using univariate and multivariate logistic regression.RESULTS: The response rate with completed surveys was 21% (346/1643). The majority of residents were male (78%), 26–35 years old (92%), in a stable relationship (70%), and without children (73%). Respondents were equally distributed across all residency years. Eighty-one percent of residents were satisfied with their career choice, although 41% had at some point given serious thought to quitting. The overall burnout rate was 67%. In the multivariate analysis, notable factors associated with burnout included inadequate operating room exposure (OR 7.57, p = 0.011), hostile faculty (OR 4.07, p = 0.008), and social stressors outside of work (OR 4.52, p = 0.008). Meaningful mentorship was protective against burnout in the multivariate regression models (OR 0.338, p = 0.031).CONCLUSIONS: Rates of burnout and career satisfaction are paradoxically high among neurosurgery trainees. While several factors were predictive of burnout, including inadequate operative exposure and social stressors, meaningful mentorship proved to be protective against burnout. The documented negative effects of burnout on patient care and health care economics necessitate further studies for potential solutions to curb its rise.

Glioblastoma multiforme (GBM) heterogeneity causes a greater number of deaths than any other brain tumor, despite the availability of alkylating chemotherapy. GBM stem-like cells (GSCs) contribute to GBM complexity and chemoresistance, but it remains challenging to identify and target GSCs or factors that control their activity. Here, we identified a specific GSC subset and show that activity of these cells is positively regulated by stabilization of methyl CpG binding domain 3 (MBD3) protein. MBD3 binds to CK1A and to BTRCP E3 ubiquitin ligase, triggering MBD3 degradation, suggesting that modulating this circuit could antagonize GBM recurrence. Accordingly, xenograft mice treated with the CK1A activator pyrvinium pamoate (Pyr-Pam) showed enhanced MBD3 degradation in cells expressing high levels of O⁶-methylguanine-DNA methyltransferase (MGMT) and in GSCs, overcoming temozolomide chemoresistance. Pyr-Pam blocked recruitment of MBD3 and the repressive nucleosome remodeling and deacetylase (NuRD) complex to neurogenesis-associated gene loci and increased acetyl–histone H3 activity and GSC differentiation. We conclude that CK1A/BTRCP/MBD3/NuRD signaling modulates GSC activation and malignancy, and that targeting this signaling could suppress GSC proliferation and GBM recurrence.