Ligand-independent integrin ß1 signaling supports lung adenocarcinoma development.

Integrins - the principal extracellular matrix (ECM) receptors of the cell - promote cell adhesion, migration, and proliferation, which are key events for cancer growth and metastasis. To date, most integrin-targeted cancer therapeutics have disrupted integrin-ECM interactions, which are viewed as critical for integrin functions. However, such agents have failed to improve cancer patient outcomes. We show that the highly expressed integrin ß1 subunit is required for lung adenocarcinoma development in a carcinogen-induced mouse model. Likewise, human lung adenocarcinoma cell lines with integrin ß1 deletion failed to form colonies in soft agar and tumors in mice. Mechanistically, we demonstrate that these effects do not require integrin ß1-mediated adhesion to ECM but are dependent on integrin ß1 cytoplasmic tail-mediated activation of focal adhesion kinase (FAK). These studies support a critical role for integrin ß1 in lung tumorigenesis that is mediated through constitutive, ECM binding-independent signaling involving the cytoplasmic tail.

Cannabinoid type 1 receptors in A2a neurons contribute to cocaine-environment association.

RATIONALE: Cannabinoid type 1 receptors (CB1Rs) are widely expressed within the brain's reward circuits and are implicated in regulating drug induced behavioral adaptations. Understanding how CB1R signaling in discrete circuits and cell types contributes to drug-related behavior provides further insight into the pathology of substance use disorders. OBJECTIVE AND METHODS: We sought to determine how cell type-specific expression of CB1Rs within striatal circuits contributes to cocaine-induced behavioral plasticity, hypothesizing that CB1R function in distinct striatal neuron populations would differentially impact behavioral outcomes. We crossed conditional Cnr1fl/fl mice and striatal output pathway cre lines (Drd1a -cre; D1, Adora2a -cre; A2a) to generate cell type-specific CB1R knockout mice and assessed their performance in cocaine locomotor and associative behavioral assays. RESULTS: Both knockout lines retained typical locomotor activity at baseline. D1-Cre x Cnr1fl/fl mice did not display hyperlocomotion in response to acute cocaine dosing, and both knockout lines exhibited blunted locomotor activity across repeated cocaine doses. A2a-cre Cnr1fl/fl, mice did not express a preference for cocaine paired environments in a two-choice place preference task. CONCLUSIONS: This study aids in mapping CB1R-dependent cocaine-induced behavioral adaptations onto distinct striatal neuron subtypes. A reduction of cocaine-induced locomotor activation in the D1- and A2a-Cnr1 knockout mice supports a role for CB1R function in the motor circuit. Furthermore, a lack of preference for cocaine-associated context in A2a-Cnr1 mice suggests that CB1Rs on A2a-neuron inhibitory terminals are necessary for either reward perception, memory consolidation, or recall. These results direct future investigations into CB1R-dependent adaptations underlying the development and persistence of substance use disorders.

Leveraging Telehealth and Medical Student Volunteers to Bridge Gaps in Education Access for Providers in Limited-Resource Settings.

PROBLEM: High-quality training opportunities for providers in limited-resource settings are often scarce or nonexistent. This can lead to a dearth of boots-on-the-ground workers capable of translating knowledge into effective action. The tested telehealth education model of Project ECHO (Extension for Community Healthcare Outcomes) can help address this disparity. However, the planning and logistical coordination required can be limiting. APPROACH: Medical student volunteers interested in health disparities and global health can be leveraged to reduce the costs of administration for Project ECHO programs. From mid-2018 to present (2020), student organizations have been formed at Vanderbilt University School of Medicine, University of California, San Francisco, School of Medicine, and Albert Einstein College of Medicine. These organizations have recruited and trained volunteers, who play an active role in assessing the needs of local clinics and providers, developing curricula, and coordinating the logistical aspects of programs. OUTCOMES: In the first 4 student-coordinated Project ECHO cohorts (2019-2020), 25 clinics in 14 countries participated, with a potential impact on over 20,000 cancer patients annually. Satisfaction with the telehealth education programs was high among local clinicians and expert educators. Students' perceived ability to conduct activities important to successfully orchestrating a telehealth education program was significantly greater among students who had coordinated one or more Project ECHO programs than among students who had yet to participate for 7 of 9 competencies. There also appears to be an additive effect of participating in additional Project ECHO programs on perceived confidence and career path intentions. NEXT STEPS: The student-led model of coordinating telehealth education programs described here can be readily expanded to medical schools across the nation and beyond. With continued expansion, efforts are needed to develop assessments that provide insights into participants' learning, track changes in patient outcomes, and provide continuing medical education credits to local clinicians.