EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer.

Phenotypic plasticity is a recognized mechanism of therapeutic resistance in prostate cancer (PCa), however current knowledge of driver mechanisms and therapeutic interventions are limited. Using genetically engineered mouse models (GEMMs) devoid of Pten and Rb1, we previously demonstrated the chromatin reprogramming factor enhancer of zeste homolog 2 (EZH2) as an important regulator of alternative transcription programs promoting phenotypic plasticity. Here, using a multi-omics approach we demonstrate that EZH2 regulates multilineage cell states dependent on the RNA binding protein Tristetraprolin (TTP) that mediates RNA stability and activation of translation.

EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer.

Phenotypic plasticity is a recognized mechanism of therapeutic resistance in prostate cancer (PCa), however current knowledge of driver mechanisms and therapeutic interventions are limited. Using genetically engineered mouse models (GEMMs) devoid of Pten and Rb1, we previously demonstrated the chromatin reprogramming factor enhancer of zeste homolog 2 (EZH2) as an important regulator of alternative transcription programs promoting phenotypic plasticity. Here, using a multi-omics approach we demonstrate that EZH2 regulates multilineage cell states dependent on the RNA binding protein Tristetraprolin (TTP) that mediates RNA stability and activation of translation.

Biological responses during high-dose protein nutrition in the critically ill: a randomized controlled trial.

Background: Reduced protein intake is associated with adverse outcomes in critically ill patients. Paradoxically, large-scale randomized controlled trials have failed to demonstrate a beneficial effect of protein supplementation, perhaps because the dose required to achieve an anabolic response is unknown, and because biological mechanisms that determine individual patient responses to nutrition are poorly understood.

Objectives: The objective of this study was to determine the effect of exogenous protein dose on whole-body protein balance (WBPB) and associated biological markers of metabolic response.

Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer.

Unlabelled: Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment (TME) and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet (HFD) rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring.

The gut microbiome-prostate cancer crosstalk is modulated by dietary polyunsaturated long-chain fatty acids.

The gut microbiota modulates response to hormonal treatments in prostate cancer (PCa) patients, but whether it influences PCa progression remains unknown. Here, we show a reduction in fecal microbiota alpha-diversity correlating with increase tumour burden in two distinct groups of hormonotherapy naïve PCa patients and three murine PCa models. Fecal microbiota transplantation (FMT) from patients with high PCa volume is sufficient to stimulate the growth of mouse PCa revealing the existence of a gut microbiome-cancer crosstalk.

CdGAP is a talin-binding protein and a target of TGF-β signaling that promotes HER2-positive breast cancer growth and metastasis.

Epithelial-to-mesenchymal transition (EMT) plays a crucial role in metastasis, which is the leading cause of death in breast cancer patients. Here, we show that Cdc42 GTPase-activating protein (CdGAP) promotes tumor formation and metastasis to lungs in the HER2-positive (HER2) murine breast cancer model. CdGAP facilitates intravasation, extravasation, and growth at metastatic sites.

Thermoneutrality and severe malaria: investigating the effect of warmer environmental temperatures on the inflammatory response and disease progression.

Introduction: Most studies using murine disease models are conducted at housing temperatures (20 - 22°C) that are sub-optimal (ST) for mice, eliciting changes in metabolism and response to disease. Experiments performed at a thermoneutral temperature (TT; 28 - 31°C) have revealed an altered immune response to pathogens and experimental treatments in murine disease model that have implications for their translation to clinical research. How such conditions affect the inflammatory response to infection with Plasmodium berghei ANKA (PbA) and disease progression is unknown.

SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation.

SOCS1 deficiency, which increases susceptibility to hepatocellular carcinoma (HCC), promotes CDKN1A expression in the liver. High CDKN1A expression correlates with disease severity in many cancers. Here, we demonstrate a crucial pathogenic role of CDKN1A in diethyl nitrosamine (DEN)-induced HCC in SOCS1-deficient mice.

To bind or not to bind: Cistromic reprogramming in prostate cancer.

The term "cistrome" refers to the genome-wide location of regulatory elements associated with transcription factor binding-sites. The cistrome of key regulatory factors in prostate cancer etiology are substantially reprogrammed and altered during prostatic transformation and disease progression. For instance, the cistrome of the androgen receptor (AR), a ligand-inducible transcription factor central in normal prostate epithelium biology, is directly impacted and substantially reprogrammed during malignant transformation.

The Extracellular Matrix Stiffening: A Trigger of Prostate Cancer Progression and Castration Resistance?

Despite advancements made in diagnosis and treatment, prostate cancer remains the second most diagnosed cancer among men worldwide in 2020, and the first in North America and Europe. Patients with localized disease usually respond well to first-line treatments, however, up to 30% develop castration-resistant prostate cancer (CRPC), which is often metastatic, making this stage of the disease incurable and ultimately fatal. Over the last years, interest has grown into the extracellular matrix (ECM) stiffening as an important mediator of diseases, including cancers.

Response to supraphysiological testosterone is predicted by a distinct androgen receptor cistrome.

The androgen receptor (AR) is a master transcription factor that regulates prostate cancer (PC) development and progression. Inhibition of AR signaling by androgen deprivation is the first-line therapy with initial efficacy for advanced and recurrent PC. Paradoxically, supraphysiological levels of testosterone (SPT) also inhibit PC progression.

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets.

c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression.

Protein tyrosine phosphatase 1B regulates miR-208b-argonaute 2 association and thyroid hormone responsiveness in cardiac hypertrophy.

Increased production of reactive oxygen species plays an essential role in the pathogenesis of several diseases, including cardiac hypertrophy. In our search to identify redox-sensitive targets that contribute to redox signaling, we found that protein tyrosine phosphatase 1B (PTP1B) was reversibly oxidized and inactivated in hearts undergoing hypertrophy. Cardiomyocyte-specific deletion of PTP1B in mice (PTP1B cKO mice) caused a hypertrophic phenotype that was exacerbated by pressure overload.

CdGAP promotes prostate cancer metastasis by regulating epithelial-to-mesenchymal transition, cell cycle progression, and apoptosis.

High mortality of prostate cancer patients is primarily due to metastasis. Understanding the mechanisms controlling metastatic processes remains essential to develop novel therapies designed to prevent the progression from localized disease to metastasis. CdGAP plays important roles in the control of cell adhesion, migration, and proliferation, which are central to cancer progression.

EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer.

Prostate cancers are considered to be immunologically 'cold' tumors given the very few patients who respond to checkpoint inhibitor (CPI) therapy. Recently, enrichment of interferon-stimulated genes (ISGs) predicted a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is overexpressed in prostate cancer and known to negatively regulate ISGs.

Diet-Dependent Metabolic Regulation of DNA Double-Strand Break Repair in Cancer: More Choices on the Menu.

Despite several epidemiologic and preclinical studies supporting the role of diet in cancer progression, the complexity of the diet-cancer link makes it challenging to deconvolute the underlying mechanisms, which remain scantly elucidated. This review focuses on genomic instability as one of the cancer hallmarks affected by diet-dependent metabolic alterations. We discuss how altered dietary intake of metabolites of the one-carbon metabolism, including methionine, folate, and vitamins B and C, can impact the methylation processes and thereby tumorigenesis.

Evidence that EZH2 Deregulation is an Actionable Therapeutic Target for Prevention of Prostate Cancer.

Chemoprevention trials for prostate cancer by androgen receptor or androgen synthesis inhibition have proven ineffective. Recently, it has been demonstrated that the histone methlytransferase, EZH2 is deregulated in mouse and human high-grade prostatic intraepithelial neoplasia (HG-PIN). Using preclinical mouse and human models of prostate cancer, we demonstrate that genetic and chemical disruption of EZH2 expression and catalytic activity reversed the HG-PIN phenotype.

Proteases and their inhibitors as prognostic factors for high-grade serous ovarian cancer.

Ovarian carcinoma is one of the most lethal malignancies, but only very few prognostic biomarkers are known. The degradome, comprising proteases, protease non-proteolytic homologues and inhibitors, have been involved in the prognosis of many cancer types, including ovarian carcinoma. The prognostic significance of the whole degradome family has not been specifically studied in high-grade serous ovarian cancer.

Transcriptional Regulation in Prostate Cancer.

Prostate cancer development involves corruption of the normal prostate transcriptional network, following deregulated expression or mutation of key transcription factors. Here, we provide an overview of the transcription factors that are important in normal prostate homeostasis (NKX3-1, p63, androgen receptor [AR]), primary prostate cancer (ETS family members, c-MYC), castration-resistant prostate cancer (AR, FOXA1), and AR-independent castration-resistant neuroendocrine prostate cancer (RB1, p53, N-MYC). We use functional (in vitro and in vivo) as well as clinical data to discuss evidence that unveils their roles in the initiation and progression of prostate cancer, with an emphasis on results of chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq).

TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup.

Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer-associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease.

Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance.

Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting that lineage plasticity facilitates therapeutic resistance. The mechanisms underlying prostate cancer lineage plasticity are incompletely understood. Studying mouse models, we demonstrate that Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation.

ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer.

Despite the initial benefits of treating HER2-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops. Here we report that lapatinib induces the degradation of the nuclear receptor ERRα, a master regulator of cellular metabolism, and that the expression of ERRα is restored in lapatinib-resistant breast cancer cells through reactivation of mTOR signalling. Re-expression of ERRα in resistant cells triggers metabolic adaptations favouring mitochondrial energy metabolism through increased glutamine metabolism, as well as ROS detoxification required for cell survival under therapeutic stress conditions.

PTP1B Deficiency Enables the Ability of a High-Fat Diet to Drive the Invasive Character of PTEN-Deficient Prostate Cancers.

Diet affects the risk and progression of prostate cancer, but the interplay between diet and genetic alterations in this disease is not understood. Here we present genetic evidence in the mouse showing that prostate cancer progression driven by loss of the tumor suppressor Pten is mainly unresponsive to a high-fat diet (HFD), but that coordinate loss of the protein tyrosine phosphatase Ptpn1 (encoding PTP1B) enables a highly invasive disease. Prostate cancer in Pten(-/-)Ptpn1(-/-) mice was characterized by increased cell proliferation and Akt activation, interpreted to reflect a heightened sensitivity to IGF-1 stimulation upon HFD feeding.