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.
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.
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.
Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated ...fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo. Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies.
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•CAF-derived NRG1 confers antiandrogen resistance in prostate cancer•Pharmacological blockade of the NRG1-HER3 axis induces tumor regression•NRG1 is upregulated in prostate stroma in patients after androgen deprivation therapy•High NRG1 activity and reduced sensitivity to second-generation antiandrogen therapy
Zhang et al. find that cancer-associated fibroblasts promote antiandrogen resistance in prostate cancer by secreting NRG1 to activate HER3 signaling in prostate cancer cells. Blockade of the NRG1/HER3 axis can re-sensitize prostate cancer models to antiandrogen therapy.
Given acquired resistance patterns to androgen deprivation therapy and second-generation androgen receptor (AR) inhibitors, it is crucial to identify and target the mechanisms by which prostate ...cancer cells persist despite AR inhibition. Previous work has shown that the upregulation and secretion of stromal-derived growth factor neuregulin 1 (NRG1) activates PI3K-AKT signaling through its binding to the HER2/HER3 receptor and promotes prostate cancer cell growth during antiandrogen treatment. Here, we determine the clinical context where this tumor microenvironment derived NRG1 impacts response to AR inhibition. Additionally, we show that selective inhibition of NRG1 mediated activation of HER2/HER3 signaling with a clinical grade bispecific humanized immunoglobulin G1, zenocutuzumab (Zeno, MCLA-128), in both in vitro and in vivo models can overcome resistance to AR-targeted therapies.
We used purified epithelial (22Pc-EP) and fibroblast (22Pc-CAF) cell lines derived the patient-derived xenograft model (CWR22Pc), which is initially castration sensitive but can progress to castration resistant. The 22Pc-EP line is endogenous PTEN wild-type (22Pc-EPWT) and PTEN knock-out cells (22Pc-EPPTEN) were generated using CRISPR-Cas9. Cells were stimulated;with either recombinant NRG1 or conditioned media derived from the 22Pc-CAFs. Lysates were collected and prepared for western blot analysis to assess for activation of downstream signaling cascades, both with and without zenocutuzumab and enzalutamide treatment. Growth assays were also performed under similar conditions. 22Pc-EPWT and 22Pc-EPPTEN; cells were co-injected subcutaneously (10:1 ratio) in the;flanks of castrated male mice then treated with either;vehicle control, castration + enzalutamide (30mg/kg/day), or enzalutmide + zenocutuzumab (25mg/kg intraperitoneal injection weekly) once tumors were established. Tumor volume was measured bi-weekly and surviving mice were sacrificed after 7 weeks of therapy.
Stimulation with recombinant NRG1 was able to activate downstream PI3K signaling in the 22Pc-EP cell lines, and this signal was more robust and sustained over time in the setting of PTEN loss. 22Pc-EPWT cells were responsive to enzalutamide and cell growth was decreased upon treatment, though this was overcome by stimulation with NRG. Treatment with zenocutuzumab restored the enzalutamide sensitive phenotype. 22Pc-EPPTEN cells were also sensitive to enzalutamide, but NRG1 stimulation paradoxically decreased cell growth and no response to zenocutuzumab was observed (Fig 1). Additionally, culturing cells with the 22Pc-CAF conditioned media conferred analogous results to recombinant NRG1 stimulation. In our in vivo experiment, enzalutamide significantly decreased tumor growth in both the PTEN wild-type and knock-out setting. However, only PTEN wild-type tumors were responsive to zenocutuzumab (Fig 2).
Here, we show that NRG1 promotes prostate cancer cell survival and resistance to AR inhibition in PTEN wild-type prostate cancer cells. Activation of downstream PI3K-AKT signaling in a prostate cancer epithelial cell line was seen after both recombinant NRG1 stimulation and culturing with cancer associated fibroblast conditioned media. This supports a paracrine mediated action of NRG1 whereby it is secreted by stromal cells in the tumor microenvironment to promote resistance through PI3K signaling. Using zenocutuzumab, a novel clinical grade inhibitor of the NRG1-HER2/3 interaction, we were able to restore an androgen sensitive phenotype in both in vitro and in vivo models in the PTEN wild-type setting. High-risk PTEN wild-type prostate cancers may therefore be an appropriate population for future clinical studies.
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