Squamous cell carcinomas (SCCs) account for the majority of cancer mortalities. Although TP63 is an established lineage-survival oncogene in SCCs, therapeutic strategies have not been developed to ...target TP63 or it's downstream effectors. In this study we demonstrate that TP63 directly regulates NRG1 expression in human SCC cell lines and that NRG1 is a critical component of the TP63 transcriptional program. Notably, we show that squamous tumors are dependent NRG1 signaling in vivo, in both genetically engineered mouse models and human xenograft models, and demonstrate that inhibition of NRG1 induces keratinization and terminal squamous differentiation of tumor cells, blocking proliferation and inhibiting tumor growth. Together, our findings identify a lineage-specific function of NRG1 in SCCs of diverse anatomic origin.
Taste buds are assemblies of elongated epithelial cells, which are innervated by gustatory nerves that transmit taste information to the brain stem. Taste cells are continuously renewed throughout ...life via proliferation of epithelial progenitors, but the molecular regulation of this process remains unknown. During embryogenesis, sonic hedgehog (SHH) negatively regulates taste bud patterning, such that inhibition of SHH causes the formation of more and larger taste bud primordia, including in regions of the tongue normally devoid of taste buds. Here, using a Cre-lox system to drive constitutive expression of SHH, we identify the effects of SHH on the lingual epithelium of adult mice. We show that misexpression of SHH transforms lingual epithelial cell fate, such that daughter cells of lingual epithelial progenitors form cell type-replete, onion-shaped taste buds, rather than non-taste, pseudostratified epithelium. These SHH-induced ectopic taste buds are found in regions of the adult tongue previously thought incapable of generating taste organs. The ectopic buds are composed of all taste cell types, including support cells and detectors of sweet, bitter, umami, salt and sour, and recapitulate the molecular differentiation process of endogenous taste buds. In contrast to the well-established nerve dependence of endogenous taste buds, however, ectopic taste buds form independently of both gustatory and somatosensory innervation. As innervation is required for SHH expression by endogenous taste buds, our data suggest that SHH can replace the need for innervation to drive the entire program of taste bud differentiation.
The hedgehog pathway is essential for certain aspects of embryonic differentiation. Abnormalities of this pathway have been found in some cases of medulloblastoma. This report describes a patient ...with a very advanced metastatic medulloblastoma that had such molecular abnormalities. The patient was treated with a small-molecule inhibitor of the hedgehog pathway. The response of the tumor to the agent was dramatic but transitory.
This report describes a patient with a very advanced metastatic medulloblastoma that had molecular abnormalities of the hedgehog pathway. The response of the tumor to GDC-0449 was dramatic but transitory.
Medulloblastoma is a malignant tumor of the cerebellum. The median age at diagnosis is 5 years, with the age range extending into young adulthood. Primary management consists of surgical resection followed by radiation therapy and chemotherapy. Current therapies have serious short-term and long-term adverse effects, including postoperative mutism, neurocognitive deficits, endocrinopathies, sterility, and the risk of secondary high-grade glioma or meningioma.
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Patients with recurrent disease after primary therapy have a particularly poor prognosis, with a median survival of less than 6 months; the 2-year survival rate among these patients is approximately 9%.
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The hedgehog pathway is an essential embryonic signaling . . .
Grking the Smoothened signal Sharpe, Hayley J; de Sauvage, Frederic J
Science signaling,
02/2018, Letnik:
11, Številka:
516
Journal Article
Recenzirano
Odprti dostop
The kinase GRK2 has been linked to the clinically important Hedgehog (HH) signaling pathway, where it is paradoxically required for signal transduction yet also promotes internalization and ...degradation of the critical HH signal transducer Smoothened. Two reports by Li
and Pusapati
in this issue of
provide new insights into the role of GRK2 in HH signaling.
The hedgehog pathway is active during embryonic development but dormant after birth. Mutations constitutively activate hedgehog genes in basal-cell carcinoma. This phase 1 trial tested the safety and ...antitumor activity of an inhibitor of the hedgehog pathway (GDC-0449) in patients with locally advanced or metastatic basal-cell carcinoma whose tumors were inoperable or had not responded to previous therapy. The drug appeared to have antitumor activity in patients with basal-cell carcinoma.
This phase 1 trial tested the safety and antitumor activity of an inhibitor of the hedgehog pathway (GDC-0449) in patients with locally advanced or metastatic basal-cell carcinoma whose tumors were inoperable or had not responded to previous therapy. The drug appeared to have antitumor activity in patients with basal-cell carcinoma.
Basal-cell carcinoma, the most common skin cancer in the United States, has an estimated annual incidence of 0.1 to 0.5%.
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,
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The disease is largely caused by exposure to ultraviolet radiation, but there are other risk factors.
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,
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Surgery cures most cases of basal-cell carcinoma, but in a few patients there is progression to life-threatening, unresectable, locally advanced
5
,
6
or metastatic
7
,
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tumors. There is no standard therapy for locally advanced or metastatic basal-cell carcinoma. The survival time in metastatic basal-cell carcinoma varies widely, but the median is 8 months.
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Basal-cell carcinoma is associated with mutations in components of . . .
The Hedgehog (Hh) signaling pathway is inappropriately activated in certain human cancers, including medulloblastoma, an aggressive brain tumor. GDC-0449, a drug that inhibits Hh signaling by ...targeting the serpentine receptor Smoothened (SMO), has produced promising anti-tumor responses in early clinical studies of cancers driven by mutations in this pathway. To evaluate the mechanism of resistance in a medulloblastoma patient who had relapsed after an initial response to GDC-0449, we determined the mutational status of Hh signaling genes in the tumor after disease progression. We identified an amino acid substitution at a conserved aspartic acid residue of SMO that had no effect on Hh signaling but disrupted the ability of GDC-0449 to bind SMO and suppress this pathway. A mutation altering the same amino acid also arose in a GDC-0449-resistant mouse model of medulloblastoma. These findings show that acquired mutations in a serpentine receptor with features of a G protein-coupled receptor can serve as a mechanism of drug resistance in human cancer.
The intestinal epithelium has high intrinsic turnover rate, and the precise renewal of the epithelium is dependent on the microenvironment. The intestine is innervated by a dense network of ...peripheral nerves that controls various aspects of intestinal physiology. However, the role of neurons in regulating epithelial cell regeneration remains largely unknown. Here, we investigated the effects of gut-innervating adrenergic nerves on epithelial cell repair following irradiation (IR)-induced injury. We observed that adrenergic nerve density in the small intestine increased post IR, while chemical adrenergic denervation impaired epithelial regeneration. Single-cell RNA sequencing experiments revealed a decrease in IL-22 signaling post IR in denervated animals. Combining pharmacologic and genetic tools, we demonstrate that β-adrenergic receptor signaling drives IL-22 production from type 3 innate lymphoid cells (ILC3s) post IR, which in turn promotes epithelial regeneration. These results define an adrenergic-ILC3 axis important for intestinal regeneration.
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•Adrenergic denervation impairs intestinal regeneration post IR-induced injury•scRNA-seq reveals a reduction in epithelial IL-22 signaling upon denervation•IL-22 levels from ILC3s post injury are regulated downstream of β-adrenergic receptors•IL-22 mediates the effects of adrenergic nerves on intestinal regeneration
Wang and colleagues reveal a neuroimmune crosstalk important for intestinal regeneration. Upon irradiation-induced injury, adrenergic neurons increase density in the intestine and contribute to epithelial cell recovery through regulation of IL-22 production from type 3 innate lymphoid cells (ILC3s), downstream of β-adrenergic receptors.
In many organ systems such as the skin, gastrointestinal tract and hematopoietic system, homeostasis is dependent on the continuous generation of differentiated progeny from stem cells. The rodent ...incisor, unlike human teeth, grows throughout the life of the animal and provides a prime example of an organ that rapidly deteriorates if newly differentiated cells cease to form from adult stem cells. Hedgehog (Hh) signaling has been proposed to regulate self-renewal, survival, proliferation and/or differentiation of stem cells in several systems, but to date there is little evidence supporting a role for Hh signaling in adult stem cells. We used in vivo genetic lineage tracing to identify Hh-responsive stem cells in the mouse incisor and we show that sonic hedgehog (SHH), which is produced by the differentiating progeny of the stem cells, signals to several regions of the incisor. Using a hedgehog pathway inhibitor (HPI), we demonstrate that Hh signaling is not required for stem cell survival but is essential for the generation of ameloblasts, one of the major differentiated cell types in the tooth, from the stem cells. These results therefore reveal the existence of a positive-feedback loop in which differentiating progeny produce the signal that in turn allows them to be generated from stem cells.
Interleukin 27 (IL-27) was first characterized as a proinflammatory cytokine with T helper type 1-inducing activity. However, subsequent work has demonstrated that mice deficient in IL-27 receptor ...(IL-27R alpha) show exacerbated inflammatory responses to a variety of challenges, suggesting that IL-27 has important immunoregulatory functions in vivo. Here we demonstrate that IL-27R alpha-deficient mice were hypersusceptible to experimental autoimmune encephalomyelitis and generated more IL-17-producing T helper cells. IL-27 acted directly on effector T cells to suppress the development of IL-17-producing T helper cells mediated by IL-6 and transforming growth factor-beta. This suppressive activity was dependent on the transcription factor STAT1 and was independent of interferon-gamma. Finally, IL-27 suppressed IL-6-mediated T cell proliferation. These data provide a mechanistic explanation for the IL-27-mediated immune suppression noted in several in vivo models of inflammation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ligand-dependent activation of the hedgehog (Hh) signalling pathway has been associated with tumorigenesis in a number of human tissues. Here we show that, although previous reports have described a ...cell-autonomous role for Hh signalling in these tumours, Hh ligands fail to activate signalling in tumour epithelial cells. In contrast, our data support ligand-dependent activation of the Hh pathway in the stromal microenvironment. Specific inhibition of Hh signalling using small molecule inhibitors, a neutralizing anti-Hh antibody or genetic deletion of smoothened (Smo) in the mouse stroma results in growth inhibition in xenograft tumour models. Taken together, these studies demonstrate a paracrine requirement for Hh ligand signalling in the tumorigenesis of Hh-expressing cancers and have important implications for the development of Hh pathway antagonists in cancer.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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