Biology subjects

Wren, J. D.

Publications and source records attributed to Wren, J. D..

17 recordsLinked to original sources

bioRxiv2026

Tetraspanin changes in septic blood are organized by cell type, with monocyte CD82 induction and leukocyte CD37 loss associated with mortality

Background: Tetraspanins organize membrane domains that regulate inflammation. The antagonistic pair CD82 (pro-inflammatory, pro-leakage) and CD151 (anti-inflammatory, anti-leakage) coordinate endothelial activation and dysfunction in severe inflammation such as sepsis. Whether blood-cell tetraspanin networks are reorganized cell-type-specifically in human sepsis and relate to mortality is unknown. Methods: We integrated bulk meta-analysis (8 ICU-sampled cohorts, 241 controls, 550 sepsis), 28-day survival analysis (GSE65682, n=468), single-cell RNA-sequencing (3 datasets, 1.6 million PBMCs from 184 donors), co-expression networks (WGCNA), immune deconvolution with composition-adjusted survival, and mortality prediction models judged against matched random-gene controls. Mendelian randomization tested whether inherited variation in tetraspanin expression alters sepsis susceptibility. Single-cell RNA-sequencing of LPS-challenged mouse lung provided an orthogonal test. Results: Thirteen of 33 tetraspanins changed significantly in septic blood (up: CD63, CD82, CD151, ROM1, TSPAN9, UPK1A; down: CD81, TSPAN3, TSPAN13, TSPAN32, TSPAN18, TSPAN4, TSPAN31), and the direction of change followed myeloid versus lymphoid lineage restriction, reflecting the leukocyte composition shift of sepsis. WGCNA placed CD82 and CD151 in distinct modules. The CD82:CD151 ratio did not predict 28-day mortality (HR=1.09, p=0.37). In the discovery cohort, CD37 was the strongest survival-associated tetraspanin (HR=0.72 per SD, FDR=0.002), even after adjusting for leukocyte composition (HR=0.70, p=0.007). Single-cell analysis of three datasets resolved two cell-type-specific programs, monocyte CD82 up-regulation and pan-leukocyte CD37 loss. CD37 expression was directionally protective in all three independent ICU cohorts, significantly so only in the largest. Mendelian randomization found no evidence that genetically proxied baseline tetraspanin expression affects sepsis susceptibility (0 of 24 genes). In mouse lung, we found macrophage CD82 increased and endothelial CD151 decreased after LPS. Conclusions: Blood-cell tetraspanin networks are reorganized cell-type-specifically in sepsis. Much of the bulk signal reflects leukocyte composition rather than a coordinated membrane program. The CD82/CD151 antagonism, established in endothelium, is not captured by whole-blood ratios, in which the two genes reflect different cell types.

immunology↗

bioRxiv2025

Hepatocyte MLKL Drives Obesity-Driven Hepatocellular Carcinoma Progression via Mitochondrial Dysfunction Independent of Necroptosis in MASLD

Background and AimsMetabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of hepatocellular carcinoma (HCC), particularly in obesity, yet mechanisms linking hepatocyte dysfunction to tumorigenesis remain unclear. Mixed lineage kinase domain-like protein (MLKL), the effector of necroptosis, is elevated in MASLD, but its hepatocyte-intrinsic role in obesity-driven MASLD-HCC is unknown. Approach and ResultsUsing a long-term Western diet (WD)-induced MASLD-HCC model in hepatocyte-specific MLKL knockout (MlklHepKO) mice, we defined MLKLs hepatocyte-intrinsic function. WD increased hepatocyte MLKL protein expression without detectable necroptosis activation, indicating a necroptosis-independent role. MLKL deficiency did not alter WD-induced inflammation, fibrosis, or liver injury but increased hepatic lipid accumulation while reducing lipotoxic lipid species and preserving mitochondrial function. WD-fed MlklHepKO mice developed fewer and smaller tumors with reduced incidence, multiplicity, proliferation, and stemness. Transcriptomic analysis revealed upregulation of mitochondrial oxidative phosphorylation pathways in MlklHepKO livers. WD suppressed the mitochondrial fusion protein and tumor suppressor MFN2, whereas MLKL deficiency restored MFN2 expression post-translationally. In HCC cells, MLKL deletion reduced proliferation, improved mitochondrial respiration, and decreased glycolysis; these effects were reversed by MFN2 deletion. MLKL localized to nuclear and mitochondrial compartments, consistent with organelle-intrinsic functions. The human MLKL inhibitor necrosulfonamide (NSA) suppressed HepG2 xenograft growth, and elevated MLKL expression in human HCC correlated with poorer overall survival. ConclusionsHepatocyte MLKL promotes MASLD-associated HCC through a non-necroptotic mechanism involving MFN2 suppression, impaired mitochondrial function, and increased tumor proliferation and stemness. These findings identify MLKL as a potential therapeutic target in MASLD-associated HCC.

cancer biology↗

bioRxiv2025

A Non-canonical Role for Hepatocyte MLKL in Promoting Mitochondrial Dysfunction and Senescence in the Aging Liver

Liver aging is characterized by chronic inflammation and metabolic dysfunction that contributes to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Necroptosis, a form of inflammatory cell death, is activated in aging livers, and genetic (Ripk3-/-or Mlkl-/- mice) or pharmacological (RIPK1 inhibitor necrostatin-1s) inhibition of necroptosis attenuates liver inflammation and pathology. However, the cell type-specific role of necroptosis in liver aging remains unclear. Given that MLKL is expressed in hepatocytes, and its expression increases with age, we generated hepatocyte-specific MLKL-overexpressing mice (MLKLHepOE) to determine its role in liver aging. Unexpectedly, MLKL overexpression in hepatocytes did not induce necroptosis, but instead upregulated markers of cellular senescence (cell cycle arrest genes and SASP factors), increased macrophage infiltration, and elevated M1 macrophage marker expression. Electron microscopy and mitochondrial analyses revealed abnormal mitochondrial morphology, elevated oxidative stress, and disrupted mitochondrial dynamics, while lipidomics demonstrated alterations in hepatic lipid metabolites. In agreement with our observations in MLKLHepOE mice, MLKL overexpression in AML12 hepatocytes impaired mitochondrial respiration, increased proinflammatory extracellular vesicle (EV) release, and induced senescence markers, without triggering cell death. Together, these findings reveal a non-lethal, non-necroptotic role for MLKL in promoting hepatocyte senescence and metabolic dysfunction via mitochondrial impairment and EV-mediated inflammation. Our study highlights MLKL as a novel driver of liver inflammaging and a potential therapeutic target for age-related liver disease.

cell biology↗

bioRxiv2024

AutoGDC: A Python Package for DNA Methylation and Transcription Meta-Analyses

AO_SCPLOWBSTRACTC_SCPLOW0.1 MotivationThe Genomic Data Commons is a powerful resource which facilitates the exploration of molecular alterations across various diseases. However, utilizing this resource for meta-analysis requires many different tools to query, download, organize, and analyze the data. In order to facilitate a more rapid, simple means of analyzing DNA methylation and RNA sequencing datasets from the GDC we developed autogdc, a python package that integrates data curation and preprocessing with meta-analysis functionality into one simplified bioinformatic pipeline. 0.2 Availability and ImplementationThe autogdc python package is available under the GPLv3 license at along with several examples of typical use-case scenarios in the form of a jupyter notebook. The data is all originally provided by the GDC, and is therefore available under the NIH Genomic Data Sharing (GDS) and NCI GDS policies.

bioinformatics↗

bioRxiv2024

Persistent homology centrality improves link prediction performance in PubMed co-occurrence networks

AO_SCPLOWBSTRACTC_SCPLOWThis paper provides a novel approach to understanding the nature of innovation and scientific progress by analyzing large-scale datasets of scientific literature. A new measure of novelty potential or disruptiveness for a set of scientific entities is proposed, based in the mathematical formalism of algebraic topology via a method called persistent homology. In this framework, understanding where academic ideas depart from the existing body of knowledge to fill knowledge gaps is key to scoring a set of entities and their potential for filling future knowledge gaps. This framework is motivated by the assumption that scientific discovery has underlying regularities that can be modeled and predicted. Our method uses a filtration, which is a type of ranking of hypergraph components along a chosen parameter. In this work two different axes are used, which constructs a growing grid of sub-hypergraphs. The axes of time (scientific knowledge evolution) and normalized point-wise mutual information (network structure) affords the ability to succinctly represent the entire dynamic structure of the scientific literature network. We then find that using very simple and interpretable measures of centrality derived from this crude bifiltration or vineyard affords the ability to predict links within the dynamic scientific network. While several different methods of link prediction have been proposed in the past, the method presented here extends the notion of link prediction to a higher dimension, as the boundary of the knowledge gap may be more than just 0-dimensional nodes. The system presented here not only suggests a mathematical basis, consistent with observations in cognitive neurosciences regarding early childhood language acquisition, but additionally provides useful applications for the scientific community in predicting and ranking hypothesis for scientific discovery.

bioinformatics↗

bioRxiv2023

Methylation Array Signals are Predictive of Chronological Age Without Bisulfite Conversion

DNA methylation data has been used to make "epigenetic clocks" which attempt to measure chronological and biological aging. These models rely on data derived from bisulfite-based measurements, which exploit a semi-selective deamination and a genomic reference to determine methylation states. Here, we demonstrate how another hallmark of aging, genomic instability, influences methylation measurements in both bisulfite sequencing and methylation arrays. We found that non-methylation factors lead to "pseudomethylation" signals that are both confounding of epigenetic clocks and uniquely age predictive. Quantifying these covariates in aging studies will be critical to building better clocks and designing appropriate studies of epigenetic aging.

molecular biology↗

bioRxiv2022

A NOVEL UNBIASED SEED-BASED RNAi SCREEN IDENTIFIES SMALL RNAs THAT INHIBIT ANDROGEN SIGNALING AND PROSTATE CANCER CELL GROWTH

Blocking androgen receptor signaling is the mainstay of therapy for advanced prostate cancer (PCa). However, acquired resistance to single agents targeting this pathway results in the development of lethal castration resistant PCa. Combination therapy approaches represent a promising strategy for the treatment of advanced disease. Here we explore a therapeutic strategy for PCa based on the ability of sh/siRNAs to function essentially as miRNAs and, via seed sequence complementarity, induce RNA interference of numerous targets simultaneously. We developed a library that contained shRNAs with all possible seed sequence combinations to identify those ones that most potently reduce cell growth and viability when expressed in PCa cells. Validation of some of these RNAi sequences indicated that the toxic effect is associated with seed sequence complementarity to the 3-UTR of AR coregulatory and essential genes. In fact, expression of siRNAs containing the identified toxic seed sequences led to global inhibition of AR-mediated gene expression and reduced expression of cell cycle genes. When tested in mice, the toxic shRNAs also inhibited castration resistant PCa and exhibited therapeutic efficacy in pre-established tumors. This multi-targeted RNAi approach may be a promising therapeutic strategy for PCa.

cancer biology↗

bioRxiv2022

Blocking necroptosis reduces inflammation and tumor incidence in a mouse model of diet-induced hepatocellular carcinoma

Background & AimsNonalcoholic fatty liver disease (NAFLD) is one of the etiologies that contribute to hepatocellular carcinoma (HCC), and chronic inflammation is one of the proposed mediators of HCC. As necroptosis is a cell death pathway that induces inflammation, we tested whether necroptosis- induced inflammation contributes to the progression of NAFLD to HCC in a mouse model of diet- induced HCC. MethodsMale and female wild-type (WT) mice or mouse models where necroptosis is blocked (Ripk3-/- or Mlkl-/- mice) were fed a control diet or choline-deficient low fat diet (CD-LFD) or CD-high fat diet (CD-HFD) for 6 months. Changes in inflammation, immune cell infiltration, activation of oncogenic pathways, and tumor incidence were assessed by gene expression analysis, western blotting, and flow cytometry. RNA sequencing (RNA-seq) was performed to assess the changes in liver transcriptome. ResultsBlocking necroptosis by deleting either Ripk3 or Mlkl reduced markers of inflammation [proinflammatory cytokines (TNF, IL-6, and IL-1{beta}), F4/80+ve macrophages, CCR2+ve infiltrating monocytes], inflammation associated oncogenic pathways (JNK, PD-L1/PD-1, {beta}-catenin), and HCC in male mice. In female mice, blocking necroptosis reduced HCC independent of inflammation. Blocking necroptosis reduced cell senescence markers in males and females, suggesting a novel cross-talk between necroptosis and cell senescence. ConclusionsOur data show that hepatic necroptosis promotes recruitment and activation of liver macrophages leading to chronic inflammation, which in turn trigger oncogenic pathways leading to the progression of NAFLD to HCC in male mice. In female mice necroptosis contributes to HCC independent of inflammation. Thus, our study suggests that necroptosis is a valid target for NAFLD-mediated HCC. SynopsisNecroptosis is a cell death pathway that mediate inflammation. Blocking necroptosis attenuated chronic inflammation by reducing recruitment and activation of liver macrophages, which in turn reduced activation of oncogenic pathways and progression of NAFLD to HCC in mice. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/502666v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1bf82d7org.highwire.dtl.DTLVardef@26fc68org.highwire.dtl.DTLVardef@18538f4org.highwire.dtl.DTLVardef@15e338b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Four novel, immortal cell lines derived from embryos of Xenopus tropicalis

The diploid anuran, Xenopus tropicalis, has emerged as a key research model in cell and developmental biology. To enhance the usefulness of this species, we developed methods for generating immortal cell lines from Nigerian strain (NXR_1018, RRID:SCR_013731) X. tropicalis embryos. We generated 14 cell lines that were propagated for several months. We selected four morphologically distinct lines, XTN-6, XTN-8, XTN-10, and XTN-12 for further characterization. Karyotype analysis revealed that three of the lines, XTN-8, XTN-10, and XTN-12 were primarily diploid. XTN-6 cultures showed a consistent mixed population of diploid cells, cells with chromosome 8 trisomy, and cells containing a tetraploid content of chromosomes. The lines were propagated using conventional culture methods as adherent cultures at 30{degrees}C in a simple, diluted L-15 medium containing fetal bovine serum without use of a high CO2 incubator. Transcriptome analysis indicated that the four lines were distinct lineages. These methods will be useful in the generation of cell lines from normal and mutant strains of X. tropicalis as well as other species of Xenopus.

cell biology↗

bioRxiv2021

The NOTCH3 Downstream Target HEYL Regulates Human Airway Epithelial Club Cell Differentiation

Basal cells (BC) are the resident stem/progenitor cells of the adult pseudostratified airway epithelium, whose differentiation program is orchestrated by the NOTCH signaling pathway. NOTCH3 receptor mediated signaling regulates BC to club cell differentiation; however, the downstream responses that regulate this process are largely unknown. In the present study we used an in vitro air-liquid interface model of the human pseudostratified airway epithelium to identify the NOTCH3-dependent downstream genes/pathways that regulate human BC to club cell differentiation. Activation of NOTCH3 signaling in BC via lentivirus-mediated over-expression of the active NOTCH3 intracellular domain (NICD3) promoted club cell differentiation. Bulk RNA-seq analysis of control vs NICD3-transduced cells, identified 692 NICD3 responsive genes enriched for pathways linked to airway epithelial biology and differentiation including Wnt/{beta}-catenin Signaling. Expression of the classical NOTCH target HEYL increased in response to NOTCH3 activation and positively correlated with expression of the club cell marker SCGB1A1. Further, using single-cell RNA-seq, we report that HEYL+ cells primarily clustered with SCGB1A1+ and NOTCH3+ cells. Moreover, HEYL protein co-localized with SCGB1A1 in ALI cultures in vitro and in the human and mouse airway epithelium in vivo. siRNA-mediated knockdown of HEYL in BC led to changes in epithelial structure including altered morphology and significant reductions in transepithelial electrical resistance and expression of tight junction related genes. Finally, HEYL knockdown significantly reduced the number of SCGB1A1+ club cells, along with a corresponding increase in KRT8+ BC-intermediate cells. Overall, our data identifies NOTCH3-HEYL signaling as a key regulator of BC to club cell differentiation.

cell biology↗

bioRxiv2020

Calorie Restriction Prevents Age-Related Changes in the Intestinal Microbiota

The effect of calorie restriction (CR) on the microbiome, fecal metabolome, and colon transcriptome of adult and old male mice was compared. Life-long CR increased microbial diversity and the Bacteriodetes/Fermicutes ratio and prevented the age-related changes in the microbiota, shifting it to a younger microbial and fecal metabolite profile in both C57BL/6JN and B6D2F1 mice. Old mice fed CR were enriched in the Rikenellaceae, S24-7 and Bacteroides families. The changes in the microbiome that occur with age and CR were initiated in the cecum and further modified in the colon. Short-term CR in adult mice had a minor effect on the microbiome but a major effect on the transcriptome of the colon mucosa. These data suggest that the primary impact of CR is on the physiological status of the gastrointestinal system, maintaining it in a more youthful state, which in turn results in a more diverse and youthful microbiome.

molecular biology↗

bioRxiv2020

Detecting potential reference list manipulation within a citation network

Although citations are used as a quantifiable, objective metric of academic influence, cases have been documented whereby references were added to a paper solely to inflate the perceived influence of a body of research. This reference list manipulation (RLM) could take place during the peer-review process (e.g., coercive citation from editors or reviewers), or prior to it (e.g., a quid-pro-quo between authors). Surveys have estimated how many people may have been affected by coercive RLM at one time or another, but it is not known how many authors engage in RLM, nor to what degree. Examining a subset of active, highly published authors (n=20,803) in PubMed, we find the frequency of non-self citations (NSC) to one author coming from one paper approximates Zipfs law. We propose the Gini Index as a simple means of quantifying skew in this distribution and test it against a series of "red flag" metrics that are expected to result from RLM attempts. We estimate between 81 (FDR <0.05) and 231 (FDR<0.10) authors are outliers on the curve, suggestive of chronic, repeated RLM. Based upon the distribution, we estimate approximately 3,284 (16%) of all authors may have engaged in RLM to some degree, possibly opportunistically. Finally, we find authors who use 18% or more of their references for self-citation are significantly more likely to have NSC Gini distortions, suggesting their desire to see their work cited carries over into their peer-review activity.

scientific communication and education↗

bioRxiv2020

SEED-MEDIATED RNA INTERFERENCE OF ANDROGEN SIGNALING AND SURVIVAL NETWORKS INDUCES CELL DEATH IN PROSTATE CANCER CELLS

Resistance to anti-androgen therapy in prostate cancer (PCa) is often driven by genetic and epigenetic aberrations in the androgen receptor (AR) and coregulators that maintain androgen signaling activity. We show that specific small RNAs downregulate expression of multiple essential and AR-coregulatory genes, leading to potent androgen signaling inhibition and PCa cell death. Expression of different sh-/siRNAs designed to target TMEFF2, preferentially reduce viability of PCa, but not benign, cells and growth of murine xenografts. Surprisingly this effect is independent of TMEFF2 expression. Transcriptomic and sh/siRNA seed sequence studies indicate that expression of these toxic shRNAs lead to downregulation of AR-coregulatory and essential genes thru mRNA 3-UTR sequence complementarity to the seed sequence of the toxic shRNAs. These findings reveal a specialized form of the Death Induced by Survival gene Elimination (DISE) mechanism in PCa cells, that we have termed Androgen Network (AN)-DISE, and suggest a novel therapeutic strategy for PCa.

cancer biology↗

bioRxiv2020

E proteins orchestrate dynamic transcriptional cascades to suppress ILC2 differentiation

The basic helix-loop-helix transcription factors collectively called E proteins powerfully suppress the differentiation of group2 innate lymphoid cells from bone marrow and thymic progenitors. Here we investigated the underlying molecular mechanisms using inducible gain and loss of function approaches in ILC2s and their precursors, respectively. Cross-examination of RNA sequencing and ATAC sequencing data obtained at different time points reveals a set of genes which are likely direct targets of E proteins. Consequently, a widespread down-regulation of chromatin accessibility occurs at a later time point, possibly due to the activation of transcriptional repressor genes such as Cbfa2t3 and Jdp2. The large number of genes repressed by gain of E protein function leads to the down-regulation of a transcriptional network important for ILC2 differentiation. SummaryDifferentiation of group 2 innate lymphoid cells is forcefully repressed by E protein transcription factors. This report elucidates how E proteins repress a transcriptional network important for ILC2 differentiation by up-regulating the expression of transcriptional repressors.

immunology↗

bioRxiv2020

Neuroretinal-derived caveolin-1 promotes endotoxin-induced inflammation in the murine retina

Chronic ocular inflammation is associated with many retinal degenerative diseases that result in vision loss. The immune-privileged environment and complex organization of retinal tissue allow for the retinas essential role in visual function processes, yet confound inquiries into cell-specific inflammatory effects that lead to retinal dysfunction and degeneration. Caveolin-1 (Cav1) is an integral membrane protein expressed in many retinal cell populations and has been implicated in retinal immune regulation. However, the direction (i.e., promotion or inhibition) in which Cav1 regulates inflammatory processes in the retina (as well as in other tissues) remains unclear. Previously, we showed that global-Cav1 depletion in the retina paradoxically resulted in reduced retinal inflammatory cytokine production with concurrent elevated retinal immune cell infiltration. We hypothesized that our previous results could be explained by cell-specific Cav1 functions in the retina. Here, we utilized our Chx10 (visual system homeobox 2)-Cre knockout model to deplete Cav1 specifically in the neural retinal (NR) compartment in order to clarify the role of neural retinal-specific Cav1 (NR-Cav1) in the retinal immune response to intravitreal LPS (lipopolysaccharide) challenge. Our data support that neural retinal-derived Cav1 promotes retinal tissue inflammation as Chx10-mediated Cav1 depletion was sufficient to suppress both retinal cytokine production and immune cell infiltration following inflammatory stimulation. Additionally, we identify Traf3 (tumor necrosis factor (TNF) receptor-associated factor 3) as a highly expressed potential immune modulator in retinal tissue that is upregulated with NR-Cav1 depletion. Furthermore, this study highlights the importance for understanding the role of Cav1 (and other proteins) in cell-specific contexts.

cell biology↗

bioRxiv2019

CSAG1 Maintains the Integrity of the Mitotic Centrosome in Cells with Defective p53

Centrosomes focus microtubules to promote mitotic spindle bipolarity, a critical requirement for balanced chromosome segregation. Comprehensive understanding of centrosome function and regulation requires a complete inventory of components. While many centrosome components have been identified, others may yet remain undiscovered. We have used a bioinformatics approach, based on \"guilt by association\" expression to identify novel mitotic components among the large group of predicted human proteins that have yet to be functionally characterized. Here we identify Chondrosarcoma-Associated Gene 1 (CSAG1) in maintaining centrosome integrity during mitosis. Depletion of CSAG1 disrupts centrosomes and leads to multipolar spindles more effectively in cells with compromised p53 function. Thus, CSAG1 may reflect a class of \"mitotic addiction\" genes whose expression is more essential in transformed cells.

cell biology↗

bioRxiv2018

A Tumor Suppressor-Regulated Cell Cycle Derived Gene Signature Is Prognostic Of Recurrence Risk In Prostate Cancer

BackgroundThe clinical behavior of prostate cancer (PCa) is variable, and while the majority of cases remain indolent, 10% of patients progress to deadly forms of the disease. Current clinical predictors used at the time of diagnosis have limitations to accurately establish progression risk. Here we describe the development of a tumor suppressor regulated, cell-cycle gene expression based prognostic signature for PCa, and validate its independent contribution to risk stratification in several radical prostatectomy (RP) patient cohorts.\n\nMethodsWe used RNA interference experiments in PCa cell lines to identify a gene expression based gene signature associated with Tmeff2, an androgen regulated, tumor suppressor gene whose expression shows remarkable heterogeneity in PCa. Gene expression was confirmed by qRT-PCR. Correlation of the signature with disease outcome (time to recurrence) was retrospectively evaluated in four geographically different cohorts of patients that underwent RP (834 samples), using multivariate logistical regression analysis. Multivariate analysis were adjusted for standard clinicopathological variables. Performance of the signature was compared to previously described gene expression based signatures using the SIgCheck software.\n\nResultsLow levels of Tmeff2 mRNA significantly (p<0.0001) correlated with reduced disease-free survival (DFS) in patients from the Memorial Sloan Kettering Cancer Center (MSKCC) dataset. We identified a panel of 11 TMEFF2 regulated cell cycle related genes (TMCC11), with strong prognostic value. TMCC11 expression was significantly associated with time to recurrence after prostatectomy in four geographically different patient cohorts (2.9[≤]HR[≥]4.1; p[≤]0.002), served as an independent indicator of poor prognosis in the four RP cohorts (1.96[≤]HR[≥]4.28; p[≤]0.032) and improved the prognostic value of standard clinicopathological markers. The prognostic ability of TMCC11 panel exceeded previously published oncogenic gene signatures (p=0.00017).\n\nConclusionsThis study provides evidence that the TMCC11 gene signature is a robust independent prognostic marker for PCa, reveals the value of using highly heterogeneously expressed genes, like Tmeff2, as guides to discover prognostic indicators, and suggests the possibility that low Tmeff2 expression marks a distinct subclass of PCa.

cancer biology↗