Immune evasion is a hallmark of KRAS-driven cancers, but the underlying causes remain unresolved. Here, we use a mouse model of pancreatic ductal adenocarcinoma to inactivate KRAS by CRISPR-mediated genome editing. We demonstrate that at an advanced tumor stage, dependence on KRAS for tumor growth is reduced and is manifested in the suppression of antitumor immunity. KRAS-deficient cells retain the ability to form tumors in immunodeficient mice. However, they fail to evade the host immune system in syngeneic wild-type mice, triggering strong antitumor response. We uncover changes both in tumor cells and host immune cells attributable to oncogenic KRAS expression. We identify BRAF and MYC as key mediators of KRAS-driven tumor immune suppression and show that loss of BRAF effectively blocks tumor growth in mice. Applying our results to human PDAC we show that lowering KRAS activity is likewise associated with a more vigorous immune environment.

A dichotomy exists regarding the role of signal transducer and activator of transcription 3 (STAT3) in cancer. Functional and genetic studies demonstrate either an intrinsic requirement for STAT3 or a suppressive effect on common types of cancer. These contrasting actions of STAT3 imply context dependency. To examine mechanisms that underlie STAT3 function in cancer, we evaluated the impact of STAT3 activity in KRAS-driven lung and pancreatic cancer. Our study defines a fundamental and previously unrecognized function of STAT3 in the maintenance of epithelial cell identity and differentiation. Loss of STAT3 preferentially associates with the acquisition of mesenchymal-like phenotypes and more aggressive tumor behavior. In contrast, persistent STAT3 activation through Tyr705 phosphorylation confers a differentiated epithelial morphology that impacts tumorigenic potential. Our results imply a mechanism in which quantitative differences of STAT3 Tyr705 phosphorylation, as compared with other activation modes, direct discrete outcomes in tumor progression.

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BackgroundPhase 3 trials supporting dextromethorphan/quinidine (DM/Q) use as a treatment for pseudobulbar affect (PBA) were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). The PRISM II study provides additional DM/Q experience with PBA secondary to dementia, stroke, or traumatic brain injury (TBI).MethodsParticipants in this open-label, multicenter, 90-day trial received DM/Q 20/10 mg twice daily. The primary outcome was the Center for Neurologic Study-Lability Scale (CNS-LS), assessing change in PBA episode frequency and severity. The CNS-LS final visit score was compared to baseline (primary analysis) and to the response in a previously conducted placebo-controlled trial with DM/Q in patients with ALS or MS. Secondary outcomes included change in PBA episode count and Clinical Global Impression of Change with respect to PBA as rated by a clinician (CGI-C) and by the patient or caregiver (PGI-C).ResultsThe study enrolled 367 participants with PBA secondary to dementia, stroke, or TBI. Mean (standard deviation [SD]) CNS-LS score improved significantly from 20.4 (4.4) at baseline to 12.8 (5.0) at Day 90/Final Visit (change, −7.7 [6.1]; P < .001, 95 % CI: −8.4, −7.0). This magnitude of improvement was consistent with DM/Q improvement in the earlier phase-3, placebo-controlled trial (mean [95 % CI] change from baseline, −8.2 [−9.4, −7.0]) and numerically exceeds the improvement seen with placebo in that study (−5.7 [−6.8, −4.7]). Reduction in PBA episode count was 72.3 % at Day 90/Final Visit compared with baseline (P < .001). Scores on CGI-C and PGI-C showed that 76.6 and 72.4 % of participants, respectively, were “much” or ”very much” improved with respect to PBA. The most frequently occurring adverse events (AEs) were diarrhea (5.4 %), headache (4.1 %), urinary tract infection (2.7 %), and dizziness (2.5 %); 9.8 % had AEs that led to discontinuation. Serious AEs were reported in 6.3 %; however, none were considered treatment related.ConclusionsDM/Q was shown to be an effective and well-tolerated treatment for PBA secondary to dementia, stroke, or TBI. The magnitude of PBA improvement was similar to that reported in patients with PBA secondary to ALS or MS, and the adverse event profile was consistent with the known safety profile of DM/Q.Trial registrationClinicaltrials.gov, NCT01799941, registered on 25 February 2013Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0609-0) contains supplementary material, which is available to authorized users.

In the rat, external urethral sphincter (EUS) activation during micturition consists of three sequential phases: 1) an increase in tonic EUS activity during passive filling and active contraction of the bladder (guarding reflex), 2) synchronized phasic activity (EUS bursting) associated with voiding, and 3) sustained tonic EUS activity that persists after bladder contraction. These phases are perturbed following spinal cord injury. The purpose of the present study was to characterize individual EUS motor unit (MU) patterns during micturition in the spinally intact and transected adult rat. EUS MU activity was recorded from either the L5 or L6 ventral root (intact) or EUS muscle (transected) during continuous flow cystometry in urethane-anesthetized adult female Sprague-Dawley rats. With the use of bladder pressure threshold and timing of activation, four distinct patterns of EUS MU activity were identified in the intact rat: low threshold sustained, medium/high threshold sustained, medium/high threshold not sustained, and burst only. In general, these MUs displayed little frequency modulation during active contraction, generated high-frequency bursts of action potentials during EUS bursting, and varied in terms of the duration of sustained tonic activity. In contrast, three general patterns of EUS MU activity were identified in the transected rat: low threshold, medium threshold, and high threshold. These MUs exhibited considerable frequency modulation during active contraction of the bladder, no bursting behavior and little to no sustained firing. The prominent frequency modulation of EUS MUs is likely due to the enhanced guarding reflex seen in EUS whole muscle electromyogram recordings in transected rats (D'Amico SC, Schuster IP, Collins WF 3rd. Exp Neurol 228: 59-68, 2011). In addition, EUS MU recruitment in transected rats more closely followed predictions by the size principle than in intact rats. This may reflect the influence of local synaptic circuits or intrinsic properties of EUS motoneurons that are active in intact rats but attenuated or absent in transected rats.