Biology subjects

Roes, M.

Publications and source records attributed to Roes, M..

4 recordsLinked to original sources

bioRxiv2023

A genome wide CRISPR screen reveals that HOXA9 promotes enzalutamide resistance in prostate cancer

Androgen receptor inhibitors are commonly used for prostate cancer treatment, but acquired resistance is a significant problem. Co-deletion of RB and p53 is common in castration resistant prostate cancers, however they are difficult to target pharmacologically. To comprehensively identify gene loss events that contribute to enzalutamide response, we performed a genome-wide CRISPR knockout screen in LNCaP prostate cancer cells. This revealed novel genes implicated in resistance that are largely unstudied. Gene loss events that confer enzalutamide sensitivity are enriched for GSEA categories related to stem cell and epigenetic regulation. We investigated the myeloid lineage stem cell factor HOXA9 as a candidate gene whose loss promotes sensitivity to enzalutamide. Cancer genomic data reveals that HOXA9 overexpression correlates with poor prognosis and characteristics of advanced prostate cancer. In cell culture, HOXA9 depletion sensitizes cells to enzalutamide, whereas overexpression drives enzalutamide resistance. Combination of the HOXA9 inhibitor DB818 with enzalutamide demonstrates synergy. This demonstrates the utility of our CRISPR screen data in discovering new approaches for treating enzalutamide resistant prostate cancer.

cancer biology↗

bioRxiv2021

Brain Networks Detectable by fMRI during On-Line Self Report of Hallucinations in Schizophrenia

An analysis of an internationally shared functional magnetic resonance imaging (fMRI) data involving healthy participants and schizophrenia patients extracted brain networks involved in listening to radio speech and capture hallucination experiences. A multidimensional analysis technique demonstrated that for radio-speech sound files, a brain network matching known auditory perception networks emerged, and importantly, displayed speech-duration-dependent hemodynamic responses (HDRs), confirming fMRI detection of these speech events. In the hallucination-capture data, although a sensorimotor (response) network emerged, it did not show hallucination-duration-dependent HDRs. We conclude that although fMRI retrieved the brain network involved in generating the motor responses indicating the start and end of an experienced hallucination, the hallucination event itself was not detected. Previous reports on brain networks detected by fMRI during hallucination capture is reviewed in this context.

neuroscience↗

bioRxiv2019

RB1 deletion in RB-pathway disrupted cells results in DNA damage and cancer progression.

Proliferative control in cancer cells is frequently disrupted by mutations in the RB-pathway. Intriguingly, RB1 mutations can arise late in tumorigenesis in cancer cells whose RB-pathway is already compromised by another mutation. In this study, we present evidence for increased DNA damage and instability in CDKN2A silenced cancer cells when RB1 mutations are induced. We generated isogenic RB1 mutant genotypes with CRISPR in a number of cell lines. Cells with even one mutant copy of RB1 have increased basal levels of DNA damage and increased mitotic errors. Elevated levels of reactive oxygen species as well as impaired homologous recombination repair underlie this DNA damage. When xenografted into immune compromised mice RB1 mutant cells exhibit an elevated propensity to seed new tumors in recipient lungs. This study offers evidence that late arising RB1 mutations can facilitate genome instability and cancer progression that are beyond the pre-existing proliferative control deficit.

cancer biology↗

bioRxiv2017

Premarin has opposing effects on spatial learning, neural activation and serum cytokine levels in middle age dependent on reproductive history

Menopause is associated with cognitive decline, and hormone therapies (HT) can improve cognition dependent on time since menopause. Previous parity also influences cognition in later life. The present study investigated how primiparity and long-term ovariectomy influence cognition, hippocampal neurogenesis, and neuronal activation in middle-aged rats in response to the HT, Premarin. Nulliparous and primiparous rats were sham-ovariectomized or ovariectomized, administered vehicle or Premarin six months later, and trained in the Morris water maze. Premarin improved spatial learning and memory in nulliparous rats, but impaired spatial and reversal learning in primiparous rats. Primiparity increased hippocampal neurogenesis, whereas Premarin treatment decreased immature neurons in both primiparous and nulliparous middle-aged rats in a region-specific manner. Moreover, Premarin increased serum TNF and KC/GRO in nulliparous, but not primiparous, rats, whereas Premarin increased zif268 expression in the CA3 region of the hippocampus in primiparous rats. Thus, primiparity alters how Premarin affects spatial learning, neuronal activation, serum cytokines, and adrenal mass. These findings have implications for the tailored treatment of age-associated cognitive decline in women.

neuroscience↗