Mutations in the transcription factor FOXA1 define a unique subset of prostate cancers but the functional consequences of these mutations and whether they confer gain or loss of function is unknown
. ...Here, by annotating the landscape of FOXA1 mutations from 3,086 human prostate cancers, we define two hotspots in the forkhead domain: Wing2 (around 50% of all mutations) and the highly conserved DNA-contact residue R219 (around 5% of all mutations). Wing2 mutations are detected in adenocarcinomas at all stages, whereas R219 mutations are enriched in metastatic tumours with neuroendocrine histology. Interrogation of the biological properties of wild-type FOXA1 and fourteen FOXA1 mutants reveals gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wild-type FOXA1, promoted an exaggerated pro-luminal differentiation program, whereas two different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) of wild-type FOXA1 and representative Wing2 and R219 mutants revealed marked, mutant-specific changes in open chromatin at thousands of genomic loci and exposed sites of FOXA1 binding and associated increases in gene expression. Of note, ATAC-seq peaks in cells expressing R219 mutants lacked the canonical core FOXA1-binding motifs (GTAAAC/T) but were enriched for a related, non-canonical motif (GTAAAG/A), which was preferentially activated by R219-mutant FOXA1 in reporter assays. Thus, FOXA1 mutations alter its pioneering function and perturb normal luminal epithelial differentiation programs, providing further support for the role of lineage plasticity in cancer progression.
Previous studies have suggested that PTEN loss is associated with p110β signaling dependency, leading to the clinical development of p110β-selective inhibitors. Here we use a panel pre-clinical ...models to reveal that PI3K isoform dependency is not governed by loss of PTEN and is impacted by feedback inhibition and concurrent PIK3CA/PIK3CB alterations. Furthermore, while pan-PI3K inhibition in PTEN-deficient tumors is efficacious, upregulation of Insulin Like Growth Factor 1 Receptor (IGF1R) promotes resistance. Importantly, we show that this resistance can be overcome through targeting AKT and we find that AKT inhibitors are superior to pan-PI3K inhibition in the context of PTEN loss. However, in the presence of wild-type PTEN and PIK3CA-activating mutations, p110α-dependent signaling is dominant and selectively inhibiting p110α is therapeutically superior to AKT inhibition. These discoveries reveal a more nuanced understanding of PI3K isoform dependency and unveil novel strategies to selectively target PI3K signaling nodes in a context-specific manner.
This paper presents a tensor analysis based method to synthesize an artificial high-resolution (HR) visual light (VIS) face image from a low-resolution (LR) near-infrared (NIR) input image captured ...from challenging operating environments. As we know, active NIR imaging has been widely employed as viable means to avoid dramatic illumination changes in outdoor circumstances. However, it exhibits discrepant photic properties in comparison with VIS imaging, and the captured images may suffer from limited quality and low resolutions resulted from uncontrolled environments and challenging imaging conditions. Based on the Lambertian reflection model and a linear observation model, we derived the framework of our approach: a tensor structure based super-resolution (SR) method is employed to transform the heterogeneous face data into uniform subspaces and conduct SR in feature space with maximum a posteriori (MAP) estimation; a discrete wavelet transform (DWT) based fusion scheme is adopted to reduce the noise and compensate for the information loss in the tensor transformation. Experiments are conducted on our collected database with JAI AD-080 multispectral camera (AD-080CL JAI, 2007) 1. Compared to the two state-of-the-art algorithms, KNN (Liu et al., 2005) 2 and LBP-KNN (Chen et al., 2009) 3, our approach shows better robustness to moderate pose and expression variations, and outstanding efficiency in dealing with images of poor quality and low resolutions.
Background
Colorectal cancer is the second‐leading cause of cancer‐related mortality in the United States and a leading cause of cancer‐related mortality worldwide. Loss of SMAD4, a critical tumor ...suppressor and the central node of the transforming growth factor‐beta superfamily, is associated with worse outcomes for colorectal cancer patients; however, it is unknown whether an RNA‐based profile associated with SMAD4 expression could be used to better identify high‐risk colorectal cancer patients.
Aim
Identify a gene expression‐based SMAD4‐modulated profile and test its association with patient outcome.
Methods and results
Using a discovery dataset of 250 colorectal cancer patients, we analyzed expression of BMP/Wnt target genes for association with SMAD4 expression. Promoters of the BMP/Wnt genes were interrogated for SMAD‐binding elements. Fifteen genes were implicated and three tested for modulation by SMAD4 in patient‐derived colorectal cancer tumoroids. Expression of the 15 genes was used for unsupervised hierarchical clustering of a training dataset and two resulting clusters modeled in a centroid model. This model was applied to an independent validation dataset of stage II and III patients. Disease‐free survival was analyzed by the Kaplan‐Meier method. In vitro analysis of three genes identified in the SMAD4‐modulated profile (JAG1, TCF7, and MYC) revealed modulation by SMAD4 consistent with the trend observed in the profile. In the training dataset (n = 553), the profile was not associated with outcome. However, among stage II and III patients (n = 461), distinct clusters were identified by unsupervised hierarchical clustering that were associated with disease‐free survival (p = .02, log‐rank test). The main model was applied to a validation dataset of stage II/III CRC patients (n = 257) which confirmed the association of clustering with disease‐free survival (p = .013, log‐rank test).
Conclusions
A SMAD4‐modulated gene expression profile identified high‐risk stage II and III colorectal cancer patients, can predict disease‐free survival, and has prognostic potential for stage II and III colorectal cancer patients.
Fusion between TMPRSS2 and ERG, placing ERG under the control of the TMPRSS2 promoter, is the most frequent genetic alteration in prostate cancer, present in 40-50% of cases. The fusion event is an ...early, if not initiating, event in prostate cancer, implicating the TMPRSS2-positive prostate epithelial cell as the cancer cell of origin in fusion-positive prostate cancer. To introduce genetic alterations into Tmprss2-positive cells in mice in a temporal-specific manner, we generated a Tmprss2-CreERT2 knock-in mouse. We found robust tamoxifen-dependent Cre activation in the prostate luminal cells but not basal epithelial cells, as well as epithelial cells of the bladder and gastrointestinal (GI) tract. The knock-in allele on the Tmprss2 locus does not noticeably impact prostate, bladder, or gastrointestinal function. Deletion of Pten in Tmprss2-positive cells of adult mice generated neoplasia only in the prostate, while deletion of Apc in these cells generated neoplasia only in the GI tract. These results suggest that this new Tmprss2-CreERT2 mouse model will be a useful resource for genetic studies on prostate and colon.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ferroptosis, a cell death process driven by iron-dependent phospholipid peroxidation, has been implicated in various diseases. There are two major surveillance mechanisms to suppress ferroptosis: one ...mediated by glutathione peroxidase 4 (GPX4) that catalyzes the reduction of phospholipid peroxides and the other mediated by enzymes, such as FSP1, that produce metabolites with free radical-trapping antioxidant activity. In this study, through a whole-genome CRISPR activation screen, followed by mechanistic investigation, we identified phospholipid-modifying enzymes MBOAT1 and MBOAT2 as ferroptosis suppressors. MBOAT1/2 inhibit ferroptosis by remodeling the cellular phospholipid profile, and strikingly, their ferroptosis surveillance function is independent of GPX4 or FSP1. MBOAT1 and MBOAT2 are transcriptionally upregulated by sex hormone receptors, i.e., estrogen receptor (ER) and androgen receptor (AR), respectively. A combination of ER or AR antagonist with ferroptosis induction significantly inhibited the growth of ER+ breast cancer and AR+ prostate cancer, even when tumors were resistant to single-agent hormonal therapies.
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•MBOAT1/2 suppress ferroptosis through phospholipid remodeling independently of GPX4•MBOAT1 and MBOAT2 are regulated by ER and AR signaling, respectively•ER antagonists sensitize ER+ breast cancer to ferroptosis by downregulating MBOAT1•AR antagonists sensitize AR+ prostate cancer to ferroptosis by downregulating MBOAT2
MBOAT1 and MBOAT2 are sex hormone-dependent ferroptosis regulators with therapeutic implications for ER+ breast cancer and AR+ prostate cancer, respectively.
Abstract
Targeted therapies for driver oncogenes have transformed the management of many cancers but the magnitude and duration of response remains variable. One potential explanation for the various ...response is the presence of additional genomic alterations which modify the degree of dependence on the targeted driver mutation. Metastatic castration resistant prostate cancer (mCRPC) serves as an example, where the target is the androgen receptor (AR). Compared to primary disease, mCRPC is characterized by extensive heterogeneity at both genomic and transcriptional levels, including genomic copy number alterations (CNAs), which are presumed to contribute to the resistance to AR targeted therapies. To gain functional insight into the genes impacted by the copy number alterations in mCRPC, we screened 730 genes often deleted in prostate cancer for CNAs that confer in vivo resistance and identified the chromodomain helicase DNA-binding protein 1 (CHD1) as a top candidate modifying resistance, a finding supported by patient data showing that CHD1 expression is inversely correlated with clinical benefit from therapy. Depletion of CHD1 in multiple human prostate cancer cell lines confers significant resistance to enzalutamide both in vitro and in vivo. Furthermore, we observed global changes in open and closed chromatin after the depletion of CHD1, indicative of an altered chromatin state, with associated changes in gene expression. Integrative analysis of ATAC-seq and RNA-seq, combining with CRISPR-based screen, identified four heterogenous resistance drivers (GR, BRN2, NR2F1, TBX2), which are elevated in different independently derived, enzalutamide-resistant, CHD1-deleted subclones. Importantly, significantly increased transcriptional heterogeneity was observed in these CHD1-depleted resistant tumors and in the tumor samples from a large mCRPC patients’ cohort. Finally, GR inhibition restored the enzalutamide sensitiivty in resistant tumors with elevated GR signaling. These results suggest CHD1-loss, through global effects on chromatin, establishes a state of plasticity that accelerates the development of AR targeted therapy resistance through activation of heterogeneous downstream effectors, which mediated the transition away from luminal lineage identity and AR dependency. This model not only provides an innovative explanation for the significantly increased transcriptional heterogeneity observed in mCRPC patients, but also suggests that proper clinical interventions targeting these heterogenous resistance drivers may be a novel avenue to prevent or even reverse resistance towards AR targeted therapies.
Citation Format: Zeda Zhang, Chuanli Zhou, Xiaoling Li, Charles Sawyers, Ping Mu. CHD1-loss promotes tumor heterogeneity and therapy resistance in prostate cancer abstract. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-117.
Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the ...drug target. We use in vitro and in vivo human prostate cancer models to show that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR)–dependent luminal epithelial cells to AR-independent basal-like cells. This lineage plasticity is enabled by the loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2, and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.
This paper discusses the stochastic stability for genetic regulatory networks (GRNs) with semi-Markov switching and time-varying delays where the transition rates (TRs) of the modes are partially ...unknown. By proposing vectors with three Legendre polynomials and three weighted Legendre polynomials, two free-matrix-based integral inequalities are derived, which involves several existing ones as their special cases. Then, two appropriate Lyapunov–Krasovskii functionals (LKFs) are established to be apt for the acquired inequalities. By introducing some free-weight matrices and utilizing the acquired integral inequalities, new sufficient conditions are proposed to ensure the stochastically asymptotic stability of analyzed networks in the mean-square sense. Finally, two simulation examples are put forward to show the effectiveness and less conservatism of the presented criteria.
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