The Hippo pathway is crucial in organ size control, and its dysregulation contributes to tumorigenesis. However, upstream signals that regulate the mammalian Hippo pathway have remained elusive. ...Here, we report that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) signaling. Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription coactivators, which are oncoproteins repressed by Lats1/2. YAP and TAZ are involved in LPA-induced gene expression, cell migration, and proliferation. In contrast, stimulation of Gs-coupled receptors by glucagon or epinephrine activates Lats1/2 kinase activity, thereby inhibiting YAP function. Thus, GPCR signaling can either activate or inhibit the Hippo-YAP pathway depending on the coupled G protein. Our study identifies extracellular diffusible signals that modulate the Hippo pathway and also establishes the Hippo-YAP pathway as a critical signaling branch downstream of GPCR.
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► LPA and S1P activate YAP/TAZ activity by inhibiting Lats kinase ► YAP/TAZ mediate physiological functions of LPA ► G12/13-, Gq/11-, and Gi/o-coupled receptors and agonists activate YAP/TAZ ► Epinephrine and glucagon inhibit YAP/TAZ via Gs-coupled GPCR signaling
GPCRs and their ligands are upstream regulators of the Hippo-YAP pathway that controls organ size and tumorigenesis.
Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of ...cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements and mutations; however, these same defects also create vulnerabilities that are relatively specific to cancer cells, which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different cancers. The therapeutic landscape of antitumour agents targeting the DDR has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATM, ATR, CHK1 and CHK2, DNA-PK and WEE1. Efforts to optimize these therapies are ongoing across a range of cancers, involving the development of predictive biomarker assays of responsiveness (beyond BRCA mutations), assessment of the mechanisms underlying intrinsic and acquired resistance, and evaluation of rational, tolerable combinations with standard-of-care treatments (such as chemotherapeutics and radiation), novel molecularly targeted agents and immune-checkpoint inhibitors. In this Review, we discuss the current status of anticancer therapies targeting the DDR.
The EGF-stimulated ERK/MAPK pathway is a key conduit for cellular proliferation signals and a therapeutic target in many cancers. Here, we characterize two central quantitative aspects of this ...pathway: the mechanism by which signal strength is encoded and the response curve relating signal output to proliferation. Under steady-state conditions, we find that ERK is activated in discrete, asynchronous pulses with frequency and duration determined by extracellular concentrations of EGF spanning the physiological range. In genetically identical sister cells, cell-to-cell variability in pulse dynamics influences the decision to enter S phase. While targeted inhibition of EGFR reduces the frequency of ERK activity pulses, inhibition of MEK reduces their amplitude. Continuous response curves measured in multiple cell lines reveal that proliferation is effectively silenced only when ERK pathway output falls below a threshold of ∼10%, indicating that high-dose targeting of the pathway is necessary to achieve therapeutic efficacy.
► ERK is activated in discrete pulses under steady-state stimulation by EGF ► The duration of ERK pulses controls entry to S phase ► Different pathway inhibitors modify the frequency or amplitude of ERK pulses ► Proliferation is stimulated preferentially by minimal levels of ERK activity
The AMP-activated protein kinase (AMPK) functions to monitor and maintain energy homeostasis at the cellular and organism level. AMPK was perceived historically primarily as a component of the ...LKB1/STK11 tumor suppressor (LKB1 mutations cause the Peutz-Jegher cancer predisposition syndrome) cascade upstream of the TSC1/2/mTOR pathway and thus likely to be a tumor suppressor. However, AMPK has recently been shown to promote cancer cell survival in the face of extrinsic and intrinsic stressors including bioenergetic, growth factor, and oncogene stress compatible with studies showing that AMPK is required for oncogenic transformation. Thus, whether AMPK acts as a bona fide tumor suppressor or a contextual oncogene and, of particular importance, whether AMPK should be targeted for activation or inhibition during cancer therapy, is controversial and requires clarification. We aim to initiate discussions of these critical questions by reviewing the role of AMPK with an emphasis on cancer cell adaptation to microenvironment stress and therapeutic intervention.
An individual's sex has been long recognized as a key factor affecting cancer incidence, prognosis, and treatment responses. However, the molecular basis for sex disparities in cancer remains poorly ...understood. We performed a comprehensive analysis of molecular differences between male and female patients in 13 cancer types of The Cancer Genome Atlas and revealed two sex-effect groups associated with distinct incidence and mortality profiles. One group contains a small number of sex-affected genes, whereas the other shows much more extensive sex-biased molecular signatures. Importantly, 53% of clinically actionable genes (60/114) show sex-biased signatures. Our study provides a systematic molecular-level understanding of sex effects in diverse cancers and suggests a pressing need to develop sex-specific therapeutic strategies in certain cancer types.
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•A rigorous, pan-cancer analysis of sex effects on molecular profiles of patients•Two sex-effect cancer groups showing distinct incidence and mortality profiles•Extensive sex-biased gene expression signatures in some cancer types•A considerable number of clinically actionable genes with sex-biased signatures
Yuan et al. perform a multidimensional analysis of molecular differences between male and female patients and classify cancer types into two groups based on sex-biased patterns. Many clinically actionable genes show sex-biased signatures in some tumor types, suggesting a need for sex-specific therapeutic strategies.
Large-scale genomic studies have identified multiple somatic aberrations in breast cancer, including copy number alterations and point mutations. Still, identifying causal variants and emergent ...vulnerabilities that arise as a consequence of genetic alterations remain major challenges. We performed whole-genome small hairpin RNA (shRNA) “dropout screens” on 77 breast cancer cell lines. Using a hierarchical linear regression algorithm to score our screen results and integrate them with accompanying detailed genetic and proteomic information, we identify vulnerabilities in breast cancer, including candidate “drivers,” and reveal general functional genomic properties of cancer cells. Comparisons of gene essentiality with drug sensitivity data suggest potential resistance mechanisms, effects of existing anti-cancer drugs, and opportunities for combination therapy. Finally, we demonstrate the utility of this large dataset by identifying BRD4 as a potential target in luminal breast cancer and PIK3CA mutations as a resistance determinant for BET-inhibitors.
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•We screened 77 breast cancer lines using a genome-wide pooled shRNA library•We developed an algorithm (siMEM) to improve identification of context-dependent genes•Integrating screen results with genomic data reveals potential “drivers”•BRD4 is essential for luminal cancer, and mutant PIK3CA confers BET-I resistance
Pooled shRNA screens of a large panel of breast cancer cell lines, coupled with an improved analytical tool, siMEM, and integration with genomic and proteomic data, identify general and context-dependent essential genes in breast cancer. This study constitutes the largest functional characterization of breast cancer to date.
PARP inhibitors (PARPi) have shown remarkable therapeutic efficacy against
-mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of ...ssDNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring
mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of
mutations. PARPi promoted accumulation of cytosolic DNA fragments because of unresolved DNA lesions, which in turn activated the DNA-sensing cGAS-STING pathway and stimulated production of type I IFNs to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade. SIGNIFICANCE: This work uncovers the mechanism behind the clinical efficacy of PARPi in patients with both BRCA-wild-type and BRCA-mutant tumors and provides a rationale for combining PARPi with immunotherapy in patients with cancer.
Immune checkpoint blockade therapies have extended patient survival across multiple cancer lineages, but there is a heated debate on whether cancer immunotherapy efficacy is different between male ...and female patients. We summarize the existing meta-analysis to show inconsistent conclusions for whether gender is associated with the immunotherapy response. We analyze molecular profiling from ICB-treated patients to identify molecular differences for immunotherapy responsiveness. We perform comprehensive analyses for patients from The Cancer Genome Atlas (TCGA) and reveal divergent patterns for sex bias in immune features across multiple cancer types. We further validate our observations in multiple independent data sets. Considering that the majority of clinical trials are in melanoma and lung cancer, meta-analyses that pool multiple cancer types have limitations to discern whether cancer immunotherapy efficacy is different between male and female patients. Future studies should include omics profiling to investigate sex-associated molecular differences in immunotherapy.
Once engaged by soluble or matrix-anchored ligands, cell surface proteins are commonly sorted to lysosomal degradation through several endocytic pathways. Defective vesicular trafficking of growth ...factor receptors, as well as unbalanced recycling of integrin- and cadherin-based adhesion complexes, has emerged in the past 5 years as a multifaceted hallmark of malignant cells. In line with the cooperative nature of endocytic machineries, multiple oncogenic alterations underlie defective endocytosis, such as altered ubiquitylation (Cbl and Nedd4 ubiquitin ligases, for example), altered cytoskeletal interactions and alterations to Rab family members. Pharmaceutical interception of the propensity of tumour cells to derail their signalling and their adhesion receptors may constitute a novel target for cancer therapy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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