Ventral tegmental area integrity measured with high-resolution 7-Tesla MRI relates to motivation across depression and anxiety diagnoses.

The ventral tegmental area (VTA) is one of the major sources of dopamine in the brain and has been associated with reward prediction, error-based reward learning, volitional drive and anhedonia. However, precise anatomical investigations of the VTA have been prevented by the use of standard-resolution MRI, reliance on subjective manual tracings, and lack of quantitative measures of dopamine-related signal. Here, we combine ultra-high field 400 µm3 quantitative MRI with dopamine-related signal mapping, and a mixture of machine learning and supervised computational techniques to delineate the VTA in a transdiagnostic sample of subjects with and without depression and anxiety disorders. Subjects also underwent cognitive testing to measure intrinsic and extrinsic motivational tone. Fifty-one subjects were scanned in total, including healthy control (HC) and mood/anxiety (MA) disorder subjects. MA subjects had significantly larger VTA volumes compared to HC but significantly lower signal intensity within VTA compared to HC, indicating reduced structural integrity of the dopaminergic VTA. Interestingly, while VTA integrity did not significantly correlate with self-reported depression or anxiety symptoms, it was correlated with an objective cognitive measure of extrinsic motivation, whereby lower VTA integrity was associated with lower motivation. This is the first study to demonstrate a computational pipeline for detecting and delineating the VTA in human subjects with 400 µm3 resolution. We highlight the use of objective transdiagnostic measures of cognitive function that link neural integrity to behavior across clinical and non-clinical groups.

An Early Examination: Psychological, Health, and Economic Correlates and Determinants of Social Distancing Amidst COVID-19.

Federal and local government agencies were quick to issue orders for residents to shelter-in-place in response to the COVID-19 outbreak. This study utilized data collected from Unacast Inc., spanning observations of 3,142 counties across 50 states and the District of Columbia (N = 230,846) from March 8, 2020 to April 13, 2020 (n = 104,930) and from April 14, 2020 to May 24, 2020 (n = 131,912) in a 3-level multilevel model to examine the correlates of social distancing behavior, as measured by the relative reduction in (1) distance traveled and (2) non-essential visitations since baseline pre-COVID-19 times. Results showed that educational attainment and political partisanship were the most consistent correlates of social distancing. State-level indicators of culture appeared to have differentiated effects depending on whether the model outcomes were reduction in general mobility or to non-essential venues. State-level neuroticism was generally positively related to social distancing, but states marked by high neuroticism were slower to engage in such behaviors. Counties and states characterized as already engaging in preventive health measures (e.g., vaccination rates, preparedness for at-risk populations) enjoyed quicker engagement in social distancing. Specific implications of findings and future directions are discussed.

Combinatorial CRISPR-Cas9 Metabolic Screens Reveal Critical Redox Control Points Dependent on the KEAP1-NRF2 Regulatory Axis.

The metabolic pathways fueling tumor growth have been well characterized, but the specific impact of transforming events on network topology and enzyme essentiality remains poorly understood. To this end, we performed combinatorial CRISPR-Cas9 screens on a set of 51 carbohydrate metabolism genes that represent glycolysis and the pentose phosphate pathway (PPP). This high-throughput methodology enabled systems-level interrogation of metabolic gene dispensability, interactions, and compensation across multiple cell types. The metabolic impact of specific combinatorial knockouts was validated using 13C and 2H isotope tracing, and these assays together revealed key nodes controlling redox homeostasis along the KEAP-NRF2 signaling axis. Specifically, targeting KEAP1 in combination with oxidative PPP genes mitigated the deleterious effects of these knockouts on growth rates. These results demonstrate how our integrated framework, combining genetic, transcriptomic, and flux measurements, can improve elucidation of metabolic network alterations and guide precision targeting of metabolic vulnerabilities based on tumor genetics.

ATF4-Induced Metabolic Reprograming Is a Synthetic Vulnerability of the p62-Deficient Tumor Stroma.

Tumors undergo nutrient stress and need to reprogram their metabolism to survive. The stroma may play a critical role in this process by providing nutrients to support the epithelial compartment of the tumor. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation by the direct control of ATF4 stability through its p62-mediated polyubiquitination. ATF4 upregulation by p62 deficiency in the stroma activates glucose carbon flux through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine generation as a source of nitrogen for stroma and tumor epithelial proliferation. Thus, p62 directly targets nuclear transcription factors to control metabolic reprogramming in the microenvironment and repress tumorigenesis, and identifies ATF4 as a synthetic vulnerability in p62-deficient tumor stroma.

Mitochondria as biosynthetic factories for cancer proliferation.

Unchecked growth and proliferation is a hallmark of cancer, and numerous oncogenic mutations reprogram cellular metabolism to fuel these processes. As a central metabolic organelle, mitochondria execute critical biochemical functions for the synthesis of fundamental cellular components, including fatty acids, amino acids, and nucleotides. Despite the extensive interest in the glycolytic phenotype of many cancer cells, tumors contain fully functional mitochondria that support proliferation and survival. Furthermore, tumor cells commonly increase flux through one or more mitochondrial pathways, and pharmacological inhibition of mitochondrial metabolism is emerging as a potential therapeutic strategy in some cancers. Here, we review the biosynthetic roles of mitochondrial metabolism in tumors and highlight specific cancers where these processes are activated.

Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis.

The tumor microenvironment plays a critical role in cancer progression, but the precise mechanisms by which stromal cells influence the epithelium are poorly understood. Here we show that p62 levels were reduced in the stroma of several tumors and that its loss in the tumor microenvironment or stromal fibroblasts resulted in increased tumorigenesis of epithelial prostate cancer cells. The mechanism involves the regulation of cellular redox through an mTORC1/c-Myc pathway of stromal glucose and amino acid metabolism, resulting in increased stromal IL-6 production, which is required for tumor promotion in the epithelial compartment. Thus, p62 is an anti-inflammatory tumor suppressor that acts through the modulation of metabolism in the tumor stroma.

Loss of myoferlin redirects breast cancer cell motility towards collective migration.

Cell migration plays a central role in the invasion and metastasis of tumors. As cells leave the primary tumor, they undergo an epithelial to mesenchymal transition (EMT) and migrate as single cells. Epithelial tumor cells may also migrate in a highly directional manner as a collective group in some settings. We previously discovered that myoferlin (MYOF) is overexpressed in breast cancer cells and depletion of MYOF results in a mesenchymal to epithelial transition (MET) and reduced invasion through extracellular matrix (ECM). However, the biomechanical mechanisms governing cell motility during MYOF depletion are poorly understood. We first demonstrated that lentivirus-driven shRNA-induced MYOF loss in MDA-MB-231 breast cancer cells (MDA-231(MYOF-KD)) leads to an epithelial morphology compared to the mesenchymal morphology observed in control (MDA-231(LTVC)) and wild-type cells. Knockdown of MYOF led to significant reductions in cell migration velocity and MDA-231(MYOF-KD) cells migrated directionally and collectively, while MDA-231(LTVC) cells exhibited single cell migration. Decreased migration velocity and collective migration were accompanied by significant changes in cell mechanics. MDA-231(MYOF-KD) cells exhibited a 2-fold decrease in cell stiffness, a 2-fold increase in cell-substrate adhesion and a 1.5-fold decrease in traction force generation. In vivo studies demonstrated that when immunocompromised mice were implanted with MDA-231(MYOF-KD) cells, tumors were smaller and demonstrated lower tumor burden. Moreover, MDA-231(MYOF-KD) tumors were highly circularized and did not invade locally into the adventia in contrast to MDA-231(LTVC)-injected animals. Thus MYOF loss is associated with a change in tumor formation in xenografts and leads to smaller, less invasive tumors. These data indicate that MYOF, a previously unrecognized protein in cancer, is involved in MDA-MB-231 cell migration and contributes to biomechanical alterations. Our results indicate that changes in biomechanical properties following loss of this protein may be an effective way to alter the invasive capacity of cancer cells.