Biology subjects

Goffin, V.

Publications and source records attributed to Goffin, V..

6 recordsLinked to original sources

bioRxiv2025

Targeting Pre-existing Club-Like Cells in Prostate Cancer Potentiates Androgen Deprivation Therapy

A critical knowledge gap in prostate cancer research is understanding whether castration-tolerant progenitor-like cells that reside in treatment-naive tumors play a direct role in therapy resistance and tumor progression. Herein, we reveal that the castration tolerance of LSCmed (Lin-, Sca-1+, CD49fmed) progenitor cells, the mouse equivalent of human prostatic Club cells, arises not from intrinsic properties, but from significant transcriptional reprogramming. Utilizing single-cell RNA sequencing of LSCmed cells isolated from prostate-specific Pten-deficient (Ptenpc-/-) mice, we identify the emergence of castration-resistant LSCmed cells enriched in stem-like features, driven by the transcription factor FOSL1/AP-1. We demonstrate that cells exhibiting Ptenpc-/- LSCmed characteristics are prevalent in aggressive double-negative prostate cancer (DNPC) subtypes recently identified in human castration-resistant prostate cancer (CRPC). Furthermore, our findings show that the dual-targeting agents JQ-1 and CX-6258--focused on FOSL1/AP-1 and PIM kinases, respectively--effectively suppress both the progenitor properties and the growth of mouse and human DNPC surrogates in vitro and in vivo. Thus, early eradication of castration-tolerant Club-like cells presents a promising therapeutic strategy to mitigate prostate cancer progression toward CRPC.

cancer biology↗

bioRxiv2024

In vitro neuroendocrine differentiation of BPH-1 cells under beta2 adrenergic receptor stimulation

Epidemiologic and experimental animal studies have shown that stress can alter tumor growth and that adrenergic fibers from the sympathetic nervous system, acting through stromal {beta}2 adrenergic receptors, promote tumor cell survival during the initial phases of cancer development. Recent epidemiological data suggest that beta blocker intake improves survival of prostate cancer patients. Hypertension and high blood pressure have been suggested to increase likelihood of prostate cancer development, suggesting that the use of beta blockers in these patients could reduce prostate cancer risk. Signaling mediated by {beta} adrenergic receptors promotes neuroendocrine differentiation in the LNCaP prostate cancer cell line. Although neuroendocrine cells are a minor population in the epithelial compartment of normal prostate glands, the population of neuroendocrine-like cells that express markers such as SYN, Bcl-2, Dll-3, and AMACR correlates with cancer progression, androgen-independent state, and poor prognosis in prostate cancer patients. As recent studies show that an increase in neuroendocrine cell density occurs before development of benign prostatic hyperplasia, a non-lethal disease affecting the transition zone, in hypertensive rats, we investigated whether neuroendocrine differentiation is associated with benign prostatic hyperplasia. Our results showed that isobutyl-methyl-xanthine, which blocks cAMP degradation, and forskolin, an adenylate cyclase activator, triggered sustained activation of the cAMP/PKA pathway and led to an increase in neuroendocrine differentiation markers in BPH-1 cells, which are a benign prostatic hyperplasia cell line. Similar results were observed by combining the {beta} adrenergic receptors agonist isoproterenol with forskolin. The same treatments reduced BPH-1 cell proliferation rates by 40% and 60%, respectively. Effects on AMACR and SYN expression and cell proliferation were fully reversed by the {beta}2 blocker carvedilol. These data suggest that {beta} adrenergic receptors are linked to the development of neuroendocrine-like cells and benign prostatic hyperplasia. As 20% of the prostate cancer tumors occur in this zone, this observation warrants further investigation.

cancer biology↗

bioRxiv2023

mTOR Inhibition Suppresses Salinomycin-Induced Ferroptosis in Breast Cancer Stem Cells by Ironing Out Mitochondrial Dysfunctions

Ferroptosis constitutes a promising therapeutic strategy against cancer by efficiently targeting the highly tumorigenic and treatment-resistant cancer stem cells (CSCs). We previously showed that the lysosomal iron-targeting drug Salinomycin (Sal) was able to eliminate CSCs by triggering ferroptosis. Here, in a well-established breast CSCs model (human mammary epithelial HMLER CD24low/CD44high), we identified that pharmacological inhibition of mechanistic target of rapamycin (mTOR), suppresses Sal-induced ferroptosis. Mechanistically, mTOR inhibition modulates iron cellular flux and prevents the iron and ROS bursts induced by Sal. Besides, integration of multi-omics data identified mitochondria as a key target of Sal action. We demonstrated that mTOR inhibition prevents Sal-induced mitochondrial functional and structural alteration, and that Sal-induced metabolic plasticity is mainly dependent on the mTOR pathway. Overall, our findings provide experimental evidences on the detailed mechanisms of mTOR as a crucial effector of Sal-induced ferroptosis, and gives proof-of-concept that careful evaluation of such combination therapy (here mTOR and ferroptosis co-targeting) is required for effective treatment. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/539040v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@8b8772org.highwire.dtl.DTLVardef@695e0forg.highwire.dtl.DTLVardef@19e3f83org.highwire.dtl.DTLVardef@5bc0a6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

STAT3 restricts prostate cancer metastasis and antiandrogen resistance by controlling LKB1/CREB signaling pathway

Prostate cancer (PCa) lethality is driven by its progression to a metastatic castration-resistant state, yet the signaling mechanisms underlying metastatic spread remain unknown. Here we show that STAT3 converges with the LKB1/mTORC1 and CREB to control metastatic disease in PCa mouse models. Unexpectedly, STAT3 was found to be upregulated in diabetic PCa patients undergoing metformin therapy with a concomitant reduction in mTORC1 expression. In preclinical mouse models of PCa, genetic ablation or activation of STAT3 had opposing effects on LKB1/AMPK/mTORC1- dependent tumorigenesis. Using genetic and pharmacological approaches, we identified LKB1 as a direct STAT3 target while repressing CREB. Furthermore, PCa patients with high CREB expression had inferior clinical outcome with significantly increased risk of disease and metastatic recurrence. We observe that castration state lowers STAT3 abundance and increases AR and CREB levels, leading to castration-resistant PCa (CRPC). Our findings revealed that STAT3 controls mTORC1 and CREB in metastatic disease, suggesting CREB as a promising target for lethal CRPC.

cancer biology↗

bioRxiv2021

In silico Computed Clusters of Prostate Luminal Progenitors Match FACS-Enriched LSCmed cells

Several groups recently published single-cell (sc) expression atlases of the adult mouse prostate cells based on RNA sequencing (scRNA-seq) data. All studies identified one computerized cluster of non-secretory luminal progenitor cells enriched in luminal and stemness-related gene transcripts. The actual correspondence between these luminal progenitor cell clusters has not been investigated. In addition, the presence of Krt4 (encoding cytokeratin 4) in these in silico-identified luminal progenitors suggested the overlap with FACS-enriched LSCmed luminal progenitor cells earlier identified as a stem-like, castration-tolerant and tumor-initiating cell population. Here, we used a unified bioinformatics pipeline to re-analyze published prostate scRNA-seq datasets and perform various pan-transcriptomic comparisons including the LSCmed cell signature. Our study demonstrates that i) the mouse prostate luminal progenitor cell clusters identified in the different scRNA-seq studies largely overlap and can be defined by a common 15-gene signature including Krt4, ii) mouse LSCmed cells match both mouse and human luminal progenitors identified by scRNA-seq analysis. Bridging these in silico-identified and ex vivo-characterized prostate luminal progenitor subsets should benefit our understanding of their actual involvement in prostate diseases.

bioinformatics↗

bioRxiv2020

Neuroendocrine mechanisms governing sex-differences in chronic pain involve prolactin receptor sensory neuron signaling

Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE2 as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE2 hypersensitivity was more persistent in females. This difference in PGE2 response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the prolactin receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using {Delta}PRL, a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female but not male mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling. Significance StatementFemales are more likely to experience chronic pain than males, but the mechanisms that underlie this sex difference are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice - where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that Prolactin receptor expression in Nav1.8+ neurons was necessary for hyperalgesic priming in female, but not male mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal prolactin receptor.

neuroscience↗