Preclinical models of prostate cancer - modelling androgen dependency and castration resistance in vitro, ex vivo and in vivo.

Prostate cancer is well known to be dependent on the androgen receptor (AR) for growth and survival. Thus, AR is the main pharmacological target to treat this disease. However, after an initially positive response to AR-targeting therapies, prostate cancer will eventually evolve to castration-resistant prostate cancer, which is often lethal. Tumour growth was initially thought to become androgen-independent following treatments; however, results from molecular studies have shown that most resistance mechanisms involve the reactivation of AR. Consequently, tumour cells become resistant to castration - the blockade of testicular androgens - and not independent of AR per se. However, confusion still remains on how to properly define preclinical models of prostate cancer, including cell lines. Most cell lines were isolated from patients for cell culture after evolution of the tumour to castration-resistant prostate cancer, but not all of these cell lines are described as castration resistant. Moreover, castration refers to the blockade of testosterone production by the testes; thus, even the concept of "castration" in vitro is questionable. To ensure maximal transfer of knowledge from scientific research to the clinic, understanding the limitations and advantages of preclinical models, as well as how these models recapitulate cancer cell androgen dependency and can be used to study castration resistance mechanisms, is essential.

Thriving through adversity: The role of passion and emotions in the resilience process.

OBJECTIVES: Two cross-sectional (Studies 1, N = 283 and 2, N = 275) and one prospective (Study 3, N = 238) studies investigated the role of passion (for academia) and emotions in the process of resilience in the education domain and in life in general. METHOD: Participants were examined when facing a stressful situation related to their passion for academia (end-of-term exam period and a timed education task). RESULTS: All three studies showed that harmonious passion, through its positive relationship with positive emotions, was positively associated with high positive outcomes in the education domain (satisfaction with one's studies, subjective and objective performance in one's studies) and in life in general via the subjective evaluation of one's life and general health indicators (subjective vitality and fewer negative physical symptoms). On the other hand, obsessive passion was related to mixed effects on resilience. Specifically, obsessive passion related to low levels of functioning (Studies 1 and 3) and also hindered the positive outcomes (Studies 1-3) through its positive relationships with positive and negative emotions, respectively. CONCLUSIONS: In sum, under stress, harmonious passion facilitates high resilience across life domains, whereas obsessive passion yields low resilience across the life or no resilience at all.

Prostate cancer resistance leads to a global deregulation of translation factors and unconventional translation.

Emerging evidence associates translation factors and regulators to tumorigenesis. However, our understanding of translational changes in cancer resistance is still limited. Here, we generated an enzalutamide-resistant prostate cancer (PCa) model, which recapitulated key features of clinical enzalutamide-resistant PCa. Using this model and poly(ribo)some profiling, we investigated global translation changes that occur during acquisition of PCa resistance. We found that enzalutamide-resistant cells exhibit an overall decrease in mRNA translation with a specific deregulation in the abundance of proteins involved in mitochondrial processes and in translational regulation. However, several mRNAs escape this translational downregulation and are nonetheless bound to heavy polysomes in enzalutamide-resistant cells suggesting active translation. Moreover, expressing these corresponding genes in enzalutamide-sensitive cells promotes resistance to enzalutamide treatment. We also found increased association of long non-coding RNAs (lncRNAs) with heavy polysomes in enzalutamide-resistant cells, suggesting that some lncRNAs are actively translated during enzalutamide resistance. Consistent with these findings, expressing the predicted coding sequences of known lncRNAs JPX, CRNDE and LINC00467 in enzalutamide-sensitive cells drove resistance to enzalutamide. Taken together, this suggests that aberrant translation of specific mRNAs and lncRNAs is a strong indicator of PCa enzalutamide resistance, which points towards novel therapeutic avenues that may target enzalutamide-resistant PCa.

KLF5 and NFYA factors as novel regulators of prostate cancer cell metabolism.

Prostate cancer (PCa) cells rely on the androgen receptor (AR) signaling axis to reprogram metabolism to sustain aberrant proliferation. Whether additional transcription factors participate to this reprogramming remains mostly unknown. To identify such factors, DNA motif analyses were performed in the promoter and regulatory regions of genes sensitive to androgens in PCa cells. These analyses identified two transcription factors, KLF5 and NFYA, as possibly associated with PCa cell metabolism. In clinical datasets, KLF5 and NFYA expression levels were associated with disease aggressiveness, being significantly decreased and increased, respectively, during PCa progression. Their expression was next investigated by qPCR and Western blot in human PCa cell models, revealing a positive regulation of KLF5 by androgens and a correlation between NFYA and AR protein expression status. siRNA-mediated knockdown of KLF5 increased human PCa cell proliferation rate in AR-positive cell models, suggesting a tumor suppressor function. Live-cell metabolic assays showed that knockdown of KLF5 promoted mitochondrial respiration, a key metabolic pathway associated with PCa progression. The opposite was observed for knockdown of NFYA regarding proliferation and respiration. RNA-seq analyses following the knockdown of either KLF5 and NFYA confirmed that both factors regulated distinct metabolic gene signatures, as well as other gene signatures, explaining their differential impact on PCa cell proliferation and metabolism. Overall, our findings identify KLF5 and NFYA as novel regulators of PCa cell metabolism.

The Role of Passion in Psychological and Cardiovascular Responses: Extending the Field of Passion and Positive Psychology in New Directions.

The present study fills a void in research on passion by examining for the first time the role of passion in physiological responses. The aim of the study was to investigate the role of passion, and the mediating role of cognitive appraisals, in the psychological and physiological responses to a stressful situation related to one's passion. Students (43 women, 12 men, M age = 27.21 years), who were passionate for their studies, completed the Passion Scale for their studies and the Cognitive Appraisal Scale (assessing perceptions of challenge/threat). Then, they engaged in an education task under stressful conditions, and a subsequent unrelated leisure task under no-stress. Physiological reactivity was measured throughout the entire session and their perceptions of situational vitality and positive and negative emotions were assessed directly after the education task. Results showed that harmonious passion (HP) positively predicted challenge appraisals that, in turn, were positively related to positive emotions, vitality, and positive cardiovascular adaptation while engaging in the stressful education task, but less so with the leisure task (unrelated to one's passion for academia). On the other hand, obsessive passion (OP) positively predicted threat appraisals. In turn, threat appraisals were positively related to negative emotions, negatively associated with vitality, and not related to cardiovascular reactivity. The present findings suggest that HP creates the onset of an adaptive psychological and physiological response whereas the response is less adaptive with OP.