TEAD transcription factors pair with YAP and TAZ to orchestrate various transcriptional programs of cell proliferation and cell death suppression that promote cancer development.The structure of TEAD ...complexed with YAP/TAZ reveals several possible avenues for pharmacological modulation, making TEAD an attractive therapeutic target.Small molecules that bind to TEAD that abrogate activity are currently being tested in clinical trials.TEAD inhibitors may be effective monotherapies for a subset of cancers driven by the YAP/TAZ–TEAD transcriptional complex.The administration of TEAD inhibitors in combination with other targeted therapies is being investigated to overcome drug resistance.
The Hippo signaling pathway inhibits the activity of the oncogenic YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif)–TEAD (TEA/ATTS domain) transcriptional complex. In cancers, inactivating mutations in upstream Hippo components and/or enhanced activity of YAP/TAZ and TEAD have been observed. The activity of this transcriptional complex can be effectively inhibited by targeting the TEAD family of transcription factors. The development of TEAD inhibitors has been driven by the discovery that TEAD has druggable hydrophobic pockets, and is currently at the clinical development stage. Three small molecule TEAD inhibitors are currently being tested in Phase I clinical trials. In this review, we highlight the role of TEADs in cancer, discuss various avenues through which TEAD activity can be inhibited, and outline the opportunities for the administration of TEAD inhibitors.
The identification of protein-protein interaction disruptors (PPIDs) that disrupt the YAP/TAZ-TEAD interaction has gained considerable momentum. Several studies have shown that YAP/TAZ are no longer ...oncogenic when their interaction with the TEAD family of transcription factors is disrupted. The transcriptional co-regulator YAP (its homolog TAZ) interact with the surface pockets of TEADs. Peptidomimetic modalities like cystine-dense peptides and YAP cyclic and linear peptides exploit surface pockets (interface 2 and interface 3) on TEADs and function as PPIDs. The TEAD surface might pose a challenge for generating an effective small molecule PPID. Interestingly, TEADs also have a central pocket that is distinct from the surface pockets, and which small molecules leverage exclusively to disrupt the YAP/TAZ-TEAD interaction (allosteric PPIDs). Although small molecules that occupy the central pocket belong to diverse classes, they display certain common features. They are flexible, which allows them to adopt a palmitate-like conformation, and they have a predominant hydrophobic portion that contacts several hydrophobic residues and a small hydrophilic portion that faces the central pocket opening. Despite such progress, more selective PPIDs that also display favorable pharmacokinetic properties and show tolerable toxicity profiles are required to evaluate the feasibility of using these PPIDs for cancer therapy.
Evidence is needed about the promptness of cancer diagnosis and associations between its measures.
We analysed data from the National Audit of Cancer Diagnosis in Primary Care 2009-10 exploring the ...association between the interval from first symptomatic presentation to specialist referral (the primary care interval, or 'interval' hereafter) and the number of pre-referral consultations.
Among 13,035 patients with any of 18 different cancers, most (82%) were referred after 1 (58%) or 2 (25%) consultations (median intervals 0 and 15 days, respectively) while 9%, 4% and 5% patients required 3, 4 or 5+ consultations (median intervals 34, 47 and 97 days, respectively) (Spearman's r=0.70). The association was at least moderate for any cancer (Spearman's r range: 0.55 (prostate)-0.77 (brain)). Patients with cancers with a higher proportion of three or more pre-referral consultations typically also had longer median intervals (e.g., multiple myeloma) and vice versa (e.g., breast cancer).
The number of pre-referral consultations has construct validity as a measure of the primary care interval. Developing interventions to reduce the number of pre-referral consultations can help improve the timeliness of cancer diagnosis, and constitutes a priority for early diagnosis initiatives and research.
Increasing evidence suggests that dietary carotenoids may reduce the risk of breast cancer. However, anti-breast cancer effects of carotenoids have been controversial, albeit understudied. Here, we ...investigated the effects of specific carotenoids on a wide range of breast cancer cell lines, and found that among several carotenoids (including β-carotene, lutein, and astaxanthin), lutein significantly inhibits breast cancer cell growth by inducing cell-cycle arrest and caspase-independent cell death, but it has little effect on the growth of primary mammary epithelial cells (PmECs). Moreover, lutein-mediated growth inhibition of breast cancer cells is quantitatively similar to that induced by chemotherapeutic taxanes, paclitaxel and docetaxel, and exposure to lutein plus taxanes additively inhibits breast cancer cell growth. Analysis of mechanisms showed that lutein treatment significantly increases the intracellular reactive oxygen species (ROS) production in triple-negative breast cancer (TNBC) cells, but not in normal PmECs. Lutein-induced growth inhibition is also attenuated by the radical oxygen scavenger
-acetyl cysteine, suggesting a role for ROS generation in the growth inhibitory effect of lutein on TNBC cells. Additionally, we found that the p53 signaling pathway is activated and HSP60 levels are increased by lutein treatment, which may contribute partly to the induction of growth inhibition in TNBC cells. Our findings show that lutein promotes growth inhibition of breast cancer cells through increased cell type-specific ROS generation and alternation of several signaling pathways. Dietary lutein supplementation may be a promising alternative and/or adjunct therapeutic candidate against breast cancer.
Sox10 : A Pan-Schwannian and Melanocytic Marker NONAKA, Daisuke; CHIRIBOGA, Luis; RUBIN, Brian P
The American journal of surgical pathology,
09/2008, Letnik:
32, Številka:
9
Journal Article
Recenzirano
S100 protein is a sensitive marker for melanomas and peripheral nerve sheath tumors. It is, however, expressed by other mesenchymal and epithelial tumors. Despite its low specificity, S100 protein is ...valuable for the diagnosis of desmoplastic melanomas and peripheral nerve sheath tumors, for which no specific marker is available. Sox10 is a neural crest transcription factor crucial for specification, maturation, and maintenance of Schwann cells and melanocytes. Anti-Sox10 antibody was applied to a variety of neural crest-derived tumors, mesenchymal and epithelial neoplasms, and normal tissues. Sox10 nuclear expression was found in 76 of 78 melanomas (97%) and 38 of 77 malignant peripheral nerve sheath tumors (49%) whereas S100 protein was expressed in 71 melanomas (91%) and 23 malignant peripheral nerve sheath tumors (30%). Sox10 was diffusely expressed in schwannomas and neurofibromas. Sox10 reaction was seen only in sustentacular cells of pheochromocytomas/paragangliomas, and occasionally carcinoid tumors from various organs, but it was not seen in the tumor cells. In normal tissues, Sox10 was expressed in Schwann cells, melanocytes, and myoepithelial cells of salivary, bronchial, and mammary glands. Sox10 reaction was not identified in any other mesenchymal and epithelial tumors except for myoepitheliomas and diffuse astrocytomas. Sox10 was expressed by metastatic melanomas and nodal capsular nevus in sentinel lymph nodes, but not by other lymph node components such as dendritic cells. Our results indicate that Sox10 will serve as a more sensitive and specific marker for the diagnosis of melanocytic and schwannian tumors than S100 protein.
Early diagnosis is an important aspect of contemporary cancer prevention and control strategies, as the majority of patients are diagnosed following symptomatic presentation. The nature of presenting ...symptoms can critically influence the length of the diagnostic intervals from symptom onset to presentation (the patient interval), and from first presentation to specialist referral (the primary care interval). Understanding which symptoms are associated with longer diagnostic intervals to help the targeting of early diagnosis initiatives is an area of emerging research. In this Review, we consider the methodological challenges in studying the presenting symptoms and intervals to diagnosis of cancer patients, and summarize current evidence on presenting symptoms associated with a range of common and rarer cancer sites. We propose a taxonomy of cancer sites considering their symptom signature and the predictive value of common presenting symptoms. Finally, we consider evidence on associations between symptomatic presentations and intervals to diagnosis before discussing implications for the design, implementation, and evaluation of public health or health system interventions to achieve the earlier detection of cancer.
Four severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants predominated in the United States since 2021. Understanding disease severity related to different SARS-CoV-2 variants ...remains limited.
Viral genome analysis was performed on SARS-CoV-2 clinical isolates circulating March 2021 through March 2022 in Cleveland, Ohio. Major variants were correlated with disease severity and patient outcomes.
In total 2779 patients identified with either Alpha (n 1153), Gamma (n 122), Delta (n 808), or Omicron variants (n 696) were selected for analysis. No difference in frequency of hospitalization, intensive care unit (ICU) admission, and death were found among Alpha, Gamma, and Delta variants. However, patients with Omicron infection were significantly less likely to be admitted to the hospital, require oxygen, or admission to the ICU (2 12.8, P .001; 2 21.6, P .002; 2 9.6, P .01, respectively). In patients whose vaccination status was known, a substantial number had breakthrough infections with Delta or Omicron variants (218/808 26.9 and 513/696 73.7, respectively). In breakthrough infections, hospitalization rate was similar regardless of variant by multivariate analysis. No difference in disease severity was identified between Omicron subvariants BA.1 and BA.2.
Disease severity associated with Alpha, Gamma, and Delta variants is comparable while Omicron infections are significantly less severe. Breakthrough disease is significantly more common in patients with Omicron infection.
Non-coding regions amplified beyond oncogene borders have largely been ignored. Using a computational approach, we find signatures of significant co-amplification of non-coding DNA beyond the ...boundaries of amplified oncogenes across five cancer types. In glioblastoma, EGFR is preferentially co-amplified with its two endogenous enhancer elements active in the cell type of origin. These regulatory elements, their contacts, and their contribution to cell fitness are preserved on high-level circular extrachromosomal DNA amplifications. Interrogating the locus with a CRISPR interference screening approach reveals a diversity of additional elements that impact cell fitness. The pattern of fitness dependencies mirrors the rearrangement of regulatory elements and accompanying rewiring of the chromatin topology on the extrachromosomal amplicon. Our studies indicate that oncogene amplifications are shaped by regulatory dependencies in the non-coding genome.
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•Enhancers active in the cell of origin are co-amplified with oncogenes•Circular extrachromosomal amplicons are associated with enhancer rewiring•Endogenous and new enhancers on amplicons contribute to cell proliferation•Skewed co-amplification that selects enhancers is found across several tumor types
Extrachromosomal oncogene amplification is a common occurrence across a broad range of cancers, yet the chromatin landscape of these high-level amplifications is poorly understood. Using a combination of approaches to explore their chromatin topology and enhancer landscape, Morton et al. observed that these oncogene amplifications are shaped by regulatory dependencies in the non-coding genome.
The WWTR1 (protein is known as TAZ)-CAMTA1 (WC) fusion gene defines epithelioid hemangioendothelioma, a malignant vascular cancer. TAZ (transcriptional coactivator with PDZ binding motif) is a ...transcriptional coactivator and end effector of the Hippo tumor suppressor pathway. It is inhibited by phosphorylation by the Hippo kinases LATS1 and LATS2. Such phosphorylation causes cytoplasmic localization, 14-3-3 protein binding and the phorphorylation of a terminal phosphodegron promotes ubiquitin-dependent degradation (the phosphorylation of the different motifs has several effects). CAMTA1 is a putative tumor suppressive transcription factor. Here we demonstrate that TAZ-CAMTA1 (TC) fusion results in its nuclear localization and constitutive activation. Consequently, cells expressing TC display a TAZ-like transcriptional program that causes resistance to anoikis and oncogenic transformation. Our findings elucidate the mechanistic basis of TC oncogenic properties, highlight that TC is an important model to understand how the Hippo pathway can be inhibited in cancer, and provide approaches for targeting this chimeric protein.
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