Biology subjects

Greenberg, A. S.

Publications and source records attributed to Greenberg, A. S..

4 recordsLinked to original sources

bioRxiv2025

Dual pathway regulation of castration response and ferroptosis in the prostate epithelium

Understanding how sex hormones maintain tissue integrity--and how their disruption can promote cancer--is a central question in biology. In the prostate, androgen signaling is crucial for development, homeostasis, and cancer, yet the molecular mechanisms underlying tissue regression after androgen-deprivation have remained unknown. Here we show that castration induces epithelial regression via ferroptosis in the normal mouse and human prostate, as well as in prostate tumors. Using in vivo analyses in genetically-engineered mice, supported by validation in human organotypic cultures, we demonstrate that androgen receptor (AR) signaling controls castration response through two distinct pathways: an intrinsic luminal epithelial pathway regulated by the prostate-specific transcription factor NKX3.1, and an extrinsic stromal signal mediated by the secreted factor pleiotrophin (PTN). Together, these AR signaling pathways coordinately regulate biosynthesis of monounsaturated fatty acid (MUFA) phospholipids and GPX4 expression to suppress prostate epithelial ferroptosis. Our findings reveal a sex hormone-regulated ferroptotic program that governs tissue homeostasis and suggest that ferroptosis induction could represent a new therapeutic strategy for prostate cancer.

developmental biology↗

bioRxiv2024

Fatty acid desaturation guides cellular decisions between ferroptosis and cellular senescence

When subject to damage or stress, cells develop responses in order to maintain tissue homeostasis. Two such decisions are ferroptosis and cellular senescence, but how cells decide between these outcomes remains unclear. Here we show that senescent cells increase levels of multiple membrane-bound polyunsaturated fatty acids (PUFAs), but a specific PUFA, dihomo-gamma-linolenic acid (DGLA, 20:3{omega}-3) is reduced. Exogenous repletion of DGLA or inhibition of delta-5-desaturase, the enzyme that metabolizes DGLA, instead results in cell death by ferroptosis. Senescent cells had elevated levels of other fezzroptosis sensitizers, including labile iron and expression of lipoxygenases - but also increased Gpx4 levels to prevent ferroptosis. Oral DGLA lowered senescent cell burden in aged mice and improved age-related functional outcomes. Finally, obese humans with lowered DGLA desaturation rates showed lower markers of adipose tissue senescence. Together, our data implicate DGLA and its desaturation as a major driver of decisions between senescence and ferroptosis.

cell biology↗

bioRxiv2020

Object-based attentional selection emerges late in visual cortical hierarchy for objects of varying perceptual strengths

Object-based attention (OBA) can - in addition to acting upon explicit object representations - act upon occluded and illusory objects. It remains unknown, however, whether or not the selection of such object representations is detectable at the same level within visual cortex. This study examined the level within visual cortex (V1-V3, LOC) at which object-based selection is observed for explicit, occluded and illusory objects. During fMRI acquisition, participants identified a target preceded by a predictive arrow cue in the double-rectangle cueing paradigm. We independently localized retinotopically-specific regions of cortex corresponding to all possible target locations to examine neural fluctuations at each level of the visual cortical hierarchy. We found, after cue onset, that activity along visual cortex was not greater for representations of cued than of uncued same object locations. In contrast, we found that activity in V3 was enhanced at retinotopic representations that correspond to uncued same than different object locations. These results, together, support attentional spreading. Additionally, when the target appeared at either the cued or uncued locations, we found higher activation in areas representing uncued same object versus cued locations. This effect emerged along the visual cortical hierarchy. Further, when the target appeared on either the cued or uncued object, we found that activation in V3 transiently increased at uncued same than different object locations. This effect was also detectable upstream in LOC. These results index attentional re-orienting between locations/objects. Effects emerged regardless of object type: explicit or completed. Thus, the gating of object information proceeds completion. Significance StatementWe investigated the level within visual cortex (V1-V3, LOC) that object-based selection is observed for explicit objects and those requiring perceptual completion. We showed that activity along visual cortex was similar for representations of locations on a cued object, which may indicate attention spreads evenly to all locations on an object marked as relevant by the cue. We also showed that activity in late visual areas was greater for representations of uncued same than different object locations, which may indicate that attention enhances the cued object. These findings support the attentional spreading account. Object selection may, thus, be instantiated by even engagement of locations within a cued, and/or suppression of locations within an uncued, object - independent of its type.

neuroscience↗

bioRxiv2020

Obesity-driven changes in ECM composition promote local invasion and metastasis of breast tumors

The extracellular matrix (ECM) is a major component of the tumor microenvironment that supports cellular growth, promotes local invasion from the primary tumor, and contributes to metastatic outgrowth in sites of colonization. Obesity is a systemic disease that causes chronic inflammation which can lead to ECM deposition and ultimately fibrosis in adipose tissues such as the mammary gland. Overweight breast cancer patients have increased metastasis to the lung and liver, exhibit resistance to chemotherapy and have worse outcomes. We found that ECM isolated from the mammary gland of both tumor-bearing and obese mice increased invasion of breast cancer cells and set out to investigate whether obesity-driven changes in ECM could identify novel drivers of invasion and metastasis in breast cancer. We performed proteomics of the mammary fat pads of both lean and obese mice and identified the entire landscape of obesity-driven ECM changes. In particular, we focused on Collagen VI, an ECM protein secreted by adipocytes in mammary tissues. Collagen VI is upregulated in the ECM of obese and tumor-bearing mice and is associated with poor outcome in human breast cancer. We found that Collagen VI drives adhesion, migration and invasion of several human breast cancer cell lines via crosstalk between the adhesion receptor NG2 and the receptor tyrosine kinase EGFR, and activation of MAPK signaling. Overall, these studies demonstrate that obesity can have profound effects on the ECM composition of tissues, which in turn can promote local invasion and metastasis.

cancer biology↗