Biology subjects

Balk, S.

Publications and source records attributed to Balk, S..

5 recordsLinked to original sources

bioRxiv2024

Androgen deprivation-mediated activation of AKT is enhanced in prostate cancer with TMPRSS2:ERG fusion

TMPRSS2:ERG gene fusion (T:E fusion) in prostate adenocarcinoma (PCa) puts ERG under androgen receptor (AR) regulated TMPRSS2 expression. T:E fusion is associated with PTEN loss, and is highly associated with decreased INPP4B expression, which together may compensate for ERG-mediated suppression of AKT signaling. We confirmed in PCa cells and a mouse PCa model that ERG suppresses IRS2 and AKT activation. In contrast, ERG downregulation did not increase INPP4B, suggesting its decrease is indirect and reflects selective pressure to suppress INPP4B function. Notably, INPP4B expression is decreased in PTEN-intact and PTEN-deficient T:E fusion tumors, suggesting selection for a nonredundant function. As ERG in T:E fusion tumors is AR regulated, we further assessed whether AR inhibition increases AKT activity in T:E fusion tumors. A T:E fusion positive PDX had increased AKT activity in vivo and response to AKT inhibition in vitro after androgen deprivation. Moreover, two clinical trials of neoadjuvant AR inhibition prior to radical prostatectomy showed greater increases in AKT activation in the T:E fusion positive versus negative tumors. These findings indicate that AKT activation may mitigate the efficacy of AR targeted therapy in T:E fusion PCa, and that these patients may most benefit from combination therapy targeting AR and AKT.

cancer biology↗

bioRxiv2024

Increased chromatin accessibility drives transition to androgen receptor splice variant dependence in castration-resistant prostate cancer

Androgen receptor (AR) splice variants, of which ARv7 is the most common, are increased in prostate cancer (PC) that develops resistance to androgen signaling inhibitor drugs, but the extent to which these variants drive AR activity, and whether they have novel functions or dependencies, remain to be determined. We generated a subline of VCaP PC cells (VCaP16) that is resistant to the AR inhibitor enzalutamide (ENZ) and found that AR activity was independent of the full-length AR (ARfl), despite its continued high-level expression, and was instead driven by ARv7. The ARv7 cistrome and transcriptome in VCaP16 cells mirrored that of the ARfl in VCaP cells, although ARv7 chromatin binding was weaker, and strong ARv7 binding sites correlated with higher affinity ARfl binding sites across multiple models and clinical samples. Notably, although ARv7 expression in VCaP cells increased rapidly in response to ENZ, there was a long lag before it gained chromatin binding and transcriptional activity. This lag was associated with an increase in chromatin accessibility, with the AR and nuclear factor I (NFI) motifs being most enriched at these more accessible sites. Moreover, the transcriptional effects of combined NFIB and NFIX knockdown versus ARv7 knockdown were highly correlated. These findings indicate that ARv7 can drive the AR program, but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding.

cancer biology↗

bioRxiv2023

Modulatory feedback explain object segmentation by attention

Studies in neuroscience inspired progress in the design of artificial neural networks (ANNs), and, vice versa, ANNs provide new insights into the functioning of brain circuits. So far, the focus has been on how ANNs can help to explain the tuning of neurons at various stages of the visual cortical hierarchy. However, the role of modulatory feedback connections, which play a role in attention and perceptual organization, has not been resolved yet. The present study presents a biologically plausible neural network that performs scene segmentation and can shift attention using modulatory feedback connections from higher to lower brain areas. The model replicates several neurophysiological signatures of recurrent processing. Specifically, figural regions elicit more activity in model units than background regions. The modulation of activity by figure and ground occurs at a delay after the first feedforward response, because it depends on a loop through the higher model areas. Importantly, the figural response enhancement is enhanced by object-based attention, which stays focused on the figural regions and does not spill over to the adjacent background, just as is observed in the visual cortex. Our results indicate how progress in artificial intelligence can be used to garner insight into the recurrent cortical processing for scene segmentation and object-based attention. Author SummaryRecent feedforward networks in artificial intelligence provide unmatched models of tuning of neurons in the visual cortex. However, these feedforward models do not explain the influences of object-based attention and image segmentation on neuronal responses, which rely on feedback interactions between cortical regions that are not included in the feedforward networks. In particular, the role of feedback connections from higher brain regions that modulate neural activity in lower cortical regions has not yet been studied extensively so that we still lack an in silico model of the role of these connections. Here, we present a biologically plausible neural network that successfully performs image segmentation and can shift object-based attention using modulatory feedback connections. The model evolved representations that mirror the properties of neurons in the visual cortex, including orientation tuning, shape-selectivity, surround suppression and a sensitivity to figure-ground organization, while trained only on a segmentation task. The new model provides insight into how the perception of coherent objects can emerge from the interaction between lower and higher visual cortical areas.

neuroscience↗

bioRxiv2021

Molecular features of exceptional response to neoadjuvant anti-androgen therapy in high-risk localized prostate cancer

High-risk localized prostate cancer (HRLPC) is associated with a substantial risk of recurrence and prostate cancer-specific mortality1. Recent clinical trials have shown that intensifying anti-androgen therapies administered prior to prostatectomy can induce pathologic complete responses (pCR) or minimal residual disease (MRD) (<5 mm), together termed exceptional response, although the molecular determinants of these clinical outcomes are largely unknown. Here, we performed whole exome (WES) and whole transcriptome sequencing (RNA-seq) on pre-treatment multi-regional tumor biopsies from exceptional responders (ER: pCR and MRD patients) and non-responders (NR: pathologic T3 or lymph node positive disease) treated with intensive anti-androgen therapies prior to prostatectomy. SPOP mutation and SPOPL copy number loss were exclusively observed in ER, while TP53 mutation and PTEN copy number loss were exclusively observed in NR. These alterations were clonal in all tumor phylogenies per patient. Additionally, transcriptional programs involving androgen signaling and TGF{beta} signaling were enriched in ER and NR, respectively. The presence of these alterations in routine biopsies from patients with HRLPC may inform the prospective identification of responders to neoadjuvant anti-androgen therapies to improve clinical outcomes and stratify other patients to alternative biologically informed treatment strategies.

cancer biology↗

bioRxiv2020

Ubiquitin Ligase MARCH5 Regulates Apoptosis through Mediation of Stress-Induced and NOXA-Dependent MCL1 Degradation

MCL1 has critical antiapoptotic functions and its levels are tightly regulated by ubiquitylation and degradation, but mechanisms that drive this degradation, particularly in solid tumors, remain to be established. We show here in prostate cancer cells that increased NOXA, mediated by activation of an integrated stress response, drives the degradation of MCL1, and identify the mitochondria-associated ubiquitin ligase MARCH5 as the primary mediator of this NOXA-dependent MCL1 degradation. Therapies that enhance MARCH5-mediated MCL1 degradation markedly enhance apoptosis in response to a BH3 mimetic agent targeting BCLXL, which may provide for a broadly effective therapy in solid tumors. Conversely, increased MCL1 in response to MARCH5 loss does not sensitize to BH3 mimetic drugs targeting MCL1, but instead also sensitizes to BCLXL inhibition, revealing a codependence between MARCH5 and MCL1 that may also be exploited in tumors with MARCH5 genomic loss.

cancer biology↗