Role of E-cadherin in metastatic brain colonization

Brain metastases are associated with a very poor prognosis and frequently occur in patients suffering from breast or colorectal cancer. During the process of metastatic colonization, successfully disseminated cancer cells settle in the brain and progress into macro-metastases. In this context, we recently summarized significant morphological differences at the macro-metastases/organ parenchyma interface (MMPI) with a strong influence on prognosis in several studies. While displacing metastases usually displayed a more favorable prognosis, infiltrative metastases had an unfavorable disease progression. Since diffuse and epithelial infiltrative cells differed in their pathophysiology, the aim of this study was to investigate the potentially responsible mechanisms underlying this difference. In our lab, we previously established a variety of brain metastasis mouse models that allow the detailed characterization of the MMPI on a morphological and molecular basis. Interestingly, diffuse and epithelial infiltrative models showed differences in their innate expression levels of the cell adhesion receptor E-cadherin across species and entities. However, we hypothesized that E-cadherin is not only a marker for the type of infiltration, but also plays a critical functional role. Thus, we performed specific opposing genetic modifications of E-cadherin in the corresponding cell lines of our brain metastasis mouse models representing the different infiltrative MMPI patterns to investigate the impact on the infiltration pattern and the metastatic microenvironment. Although both genetic approaches provoked profound phenotypic changes, they had no influence on the original characteristic of the cell. Nevertheless, the gain of E-cadherin decreased migratory and invasive capacity in vitro, while the artificial loss made cells more invasive across entities. This was reflected in the animal model with less aggressive metastases and prolonged survival after the overexpression of E-cadherin and increased aggressiveness and shortened survival in the knockdown cohorts. The switch of the infiltration pattern due to the E-cadherin modification in the metastatic outgrowth models, from diffuse to epithelial-like infiltrative after the gain of E-cadherin and the other way around after its loss, further resulted in an altered immune reaction of the metastatic microenvironment. In general, diffuse infiltrative patterns were associated with an increased immune response at the MMPI. Furthermore, we could establish a gene expression signature that clearly differentiated diffuse and epithelial infiltrative mouse models based on their metastatic cell character and even had a prognostic impact in murine and human metastases. In conclusion, these data emphasize the essential role of the MMPI during metastatic colonization of the brain and might contribute to MMPI pattern-based therapeutic decisions for cancer patients in the future. The identified gene targets could represent a prognostic tool to classify the outcome of patients with metastases based on the analysis of their tumor gene expression signature

Identification of Disparities in Personalized Cancer Care—A Joint Approach of the German WERA Consortium

(1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots—regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy

The generalization of conditioned startle responses from known to unknown lies

Throughout history, there has always been a need to find out whether people are telling the truth. Classical deception detection methods, such as polygraph-based techniques, have so far failed to accurately and reliably detect deception, as they are limited in various aspects. Therefore, results are susceptible to manipulation. In the current study, we attempt to improve lie detection using a classical conditioning procedure with startle response as an outcome variable. Thirty-six participants were asked to report true and false sentences (10 each) before the test procedure. We knew the truth value of only 50% of the sentences (the value of the other 50% was revealed after the experiment was over). Aversive conditioning was used, i.e. participants were presented with the unconditioned stimulus (air blast of 5 bar, 50 ms; contingency of 75%) when uttering known lies. There was a significant difference in participants' startle reaction to false statements compared to truths, both in the known lies category and, more importantly, in the unknown lies category. We recommend further investigation of this phenomenon by changing the conditioning parameters (duration, contingency) in order to optimize this promising method and achieve a higher level of accuracy

Endogenous IFITMs boost SARS-coronavirus 1 and 2 replication whereas overexpression inhibits infection by relocalizing ACE2

Summary: Opposing effects of interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) on SARS-CoV-2 infection have been reported. The reasons for this are unclear and the role of IFITMs in infection of other human coronaviruses (hCoVs) remains poorly understood. Here, we demonstrate that endogenous expression of IFITM2 and/or IFITM3 is critical for efficient replication of SARS-CoV-1, SARS-CoV-2 and hCoV-OC43 but has little effect on MERS-, NL63-and 229E-hCoVs. In contrast, overexpression of IFITMs inhibits all these hCoVs, and the corresponding spike-containing pseudo-particles, except OC43, which is enhanced by IFITM3. We further demonstrate that overexpression of IFITMs impairs cell surface expression of ACE2 representing the entry receptor of SARS-CoVs and hCoV-NL63 but not hCoV-OC43. Our results explain the inhibitory effects of artificial IFITM overexpression on ACE2-tropic SARS-CoVs and show that three hCoVs, including major causative agents of severe respiratory disease, hijack IFITMs for efficient infection of human cells