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Wnt/β‐catenin signalling has been suggested to be active in basal‐like breast cancer. However, in highly aggressive metastatic triple‐negative breast cancers (TNBC) the role of β‐catenin and the underlying mechanism(s) for the aggressiveness of TNBC remain unknown. We illustrate that WNT10B induces transcriptionally active β‐catenin in human TNBC and predicts survival‐outcome of patients with both TNBC and basal‐like tumours. We provide evidence that transgenic murine Wnt10b ‐driven tumours are devoid of ERα, PR and HER2 expression and can model human TNBC. Importantly, HMGA2 is specifically expressed during early stages of embryonic mammogenesis and absent when WNT10B expression is lost, suggesting a developmentally conserved mode of action. Mechanistically, ChIP analysis uncovered that WNT10B activates canonical β‐catenin signalling leading to up‐regulation of HMGA2. Treatment of mouse and human triple‐negative tumour cells with two Wnt/β‐catenin pathway modulators or siRNA to HMGA2 decreases HMGA2 levels and proliferation. We demonstrate that WNT10B has epistatic activity on HMGA2, which is necessary and sufficient for proliferation of TNBC cells. Furthermore, HMGA2 expression predicts relapse‐free‐survival and metastasis in TNBC patients. Graphical Abstract WNT10B specifically activates the canonical Wnt/i‐catenin pathway and functions as a ligand‐based model of triple‐negative mammary gland tumours that is conserved between mouse and human.

We show that activation of Wnt/β‐catenin and attenuation of Bmp signals, by combined gain‐ and loss‐of‐function mutations of β‐catenin and Bmpr1a, respectively, results in rapidly growing, aggressive squamous cell carcinomas (SCC) in the salivary glands of mice. Tumours contain transplantable and hyperproliferative tumour propagating cells, which can be enriched by fluorescence activated cell sorting (FACS). Single mutations stimulate stem cells, but tumours are not formed. We show that β‐catenin, CBP and Mll promote self‐renewal and H3K4 tri‐methylation in tumour propagating cells. Blocking β‐catenin–CBP interaction with the small molecule ICG‐001 and small‐interfering RNAs against β‐catenin, CBP or Mll abrogate hyperproliferation and H3K4 tri‐methylation, and induce differentiation of cultured tumour propagating cells into acini‐like structures. ICG‐001 decreases H3K4me3 at promoters of stem cell‐associated genes in vitro and reduces tumour growth in vivo . Remarkably, high Wnt/β‐catenin and low Bmp signalling also characterize human salivary gland SCC and head and neck SCC in general. Our work defines mechanisms by which β‐catenin signals remodel chromatin and control induction and maintenance of tumour propagating cells. Further, it supports new strategies for the therapy of solid tumours. Hyperproliferation of tumour‐propagating cells in squamous cell carcinoma depends on Wnt/β‐catenin signalling, which induces an open chromatin state and expression of self‐renewal genes.

The authors uncover a mechanism for the known antitumor effect exerted by neural precursor cells (NPCs). NPCs migrate into tumors in vivo and secrete endovanilloids, which act as agonists for TRPV1, their receptor expressed by glioma cells. TRPV1 activation causes ER stress and glioma cell death. The reported elevated concentration of TRPV1 in human gliomas and the antitumor effect of synthetic vanilloids suggest that this pathway could be a point of therapeutic intervention and that differential NPC activity, such as that modulated by age, could be a factor influencing brain tumorigenesis. Primary astrocytomas of grade 3 or 4 according to the classification system of the World Health Organization (high-grade astrocytomas or HGAs) are preponderant among adults and are almost invariably fatal despite the use of multimodal therapy. Here we show that the juvenile brain has an endogenous defense mechanism against HGAs. Neural precursor cells (NPCs) migrate to HGAs, reduce glioma expansion and prolong survival time by releasing endovanilloids that activate the vanilloid receptor (transient receptor potential vanilloid subfamily member-1 or TRPV1) on HGA cells. TRPV1 is highly expressed in tumor and weakly expressed in tumor-free brain. TRPV1 stimulation triggers tumor cell death through the branch of the endoplasmic reticulum stress pathway that is controlled by activating transcription factor-3 (ATF3). The antitumorigenic response of NPCs is lost with aging. NPC-mediated tumor suppression can be mimicked in the adult brain by systemic administration of the synthetic vanilloid arvanil, suggesting that TRPV1 agonists have potential as new HGA therapeutics.

Triple-negative breast cancers (TNBCs), which lack specific targeted therapy options, evolve into highly chemo-resistant tumors that metastasize to multiple organs simultaneously. We have previously shown that TNBCs maintain an activated WNT10B-driven network that drives metastasis. Pharmacologic inhibition by ICG-001 decreases β-catenin-mediated proliferation of multiple TNBC cell lines and TNBC patient-derived xenograft (PDX)-derived cell lines. In vitro, ICG-001 was effective in combination with the conventional cytotoxic chemotherapeutics, cisplatin and doxorubicin, to decrease the proliferation of MDA-MB-231 cells. In contrast, in TNBC PDX-derived cells doxorubicin plus ICG-001 was synergistic, while pairing with cisplatin was not as effective. Mechanistically, cytotoxicity induced by doxorubicin, but not cisplatin, with ICG-001 was associated with increased cleavage of PARP-1 in the PDX cells only. In vivo, MDA-MB-231 and TNBC PDX orthotopic primary tumors initiated de novo simultaneous multi-organ metastases, including bone metastases. WNT monotherapy blocked multi-organ metastases as measured by luciferase imaging and histology. The loss of expression of the WNT10B/β-catenin direct targets HMGA2, EZH2, AXIN2, MYC, PCNA, CCND1, transcriptionally active β-catenin, SNAIL and vimentin both in vitro and in vivo in the primary tumors mechanistically explains loss of multi-organ metastases. WNT monotherapy induced VEGFA expression in both tumor model systems, whereas increased CD31 was observed only in the MDA-MB-231 tumors. Moreover, WNT-inhibition sensitized the anticancer response of the TNBC PDX model to doxorubicin, preventing simultaneous metastases to the liver and ovaries, as well as to bone. Our data demonstrate that WNT-inhibition sensitizes TNBC to anthracyclines and treats multi-organ metastases of TNBC.

We show that activation of Wnt/[beta]-catenin and attenuation of Bmp signals, by combined gain- and loss-of-function mutations of [beta]-catenin and Bmpr1a, respectively, results in rapidly growing, aggressive squamous cell carcinomas (SCC) in the salivary glands of mice. Tumours contain transplantable and hyperproliferative tumour propagating cells, which can be enriched by fluorescence activated cell sorting (FACS). Single mutations stimulate stem cells, but tumours are not formed. We show that [beta]-catenin, CBP and Mll promote self-renewal and H3K4 tri-methylation in tumour propagating cells. Blocking [beta]-catenin-CBP interaction with the small molecule ICG-001 and small-interfering RNAs against [beta]-catenin, CBP or Mll abrogate hyperproliferation and H3K4 tri-methylation, and induce differentiation of cultured tumour propagating cells into acini-like structures. ICG-001 decreases H3K4me3 at promoters of stem cell-associated genes in vitro and reduces tumour growth in vivo. Remarkably, high Wnt/[beta]-catenin and low Bmp signalling also characterize human salivary gland SCC and head and neck SCC in general. Our work defines mechanisms by which [beta]-catenin signals remodel chromatin and control induction and maintenance of tumour propagating cells. Further, it supports new strategies for the therapy of solid tumours. [PUBLICATION ABSTRACT]

Primary astrocytomas of World Health Organization grade 3 and grade 4 (HG-astrocytomas) are preponderant among adults and are almost invariably fatal despite multimodal therapy. Here, we show that the juvenile brain has an endogenous defense mechanism against HG-astrocytomas. Neural precursor cells (NPCs) migrate to HG-astrocytomas, reduce glioma expansion and prolong survival by releasing a group of fatty acid ethanolamides that have agonistic activity on the vanilloid receptor (transient receptor potential vanilloid subfamily member-1; TRPV1). TRPV1 expression is higher in HG-astrocytomas than in tumor-free brain and TRPV1 stimulation triggers tumor cell death via the activating transcription factor-3 (ATF3) controlled branch of the ER stress pathway. The anti-tumorigenic response of NPCs is lost with aging. NPC-mediated tumor suppression can be mimicked in the adult brain by systemic administration of the synthetic vanilloid Arvanil, suggesting that TRPV1 agonists hold potential as new HG-astrocytoma therapeutics.

The three-dimensional, highly oriented pore channel anatomy of native rattan ( Calamus rotang ) was used as a template to fabricate biomorphous hydroxyapatite (Ca 5 (PO 4 ) 3 OH) ceramics designed for bone regeneration scaffolds. A low viscous hydroxyapatite-sol was prepared from triethyl phosphite and calcium nitrate tetrahydrate and repeatedly vacuum infiltrated into the native template. The template was subsequently pyrolysed at 800°C to form a biocarbon replica of the native tissue. Heat treatment at 1,300°C in air atmosphere caused oxidation of the carbon skeleton and sintering of the hydroxyapatite. SEM analysis confirmed detailed replication of rattan anatomy. Porosity of the samples measured by mercury porosimetry showed a multimodal pore size distribution in the range of 300 nm to 300 μm. Phase composition was determined by XRD and FT-IR revealing hydroxyapatite as the dominant phase with minimum fractions of CaO and Ca 3 (PO 4 ) 2 . The biomorphous scaffolds with a total porosity of 70–80% obtained a compressive strength of 3–5 MPa in axial direction and 1–2 MPa in radial direction of the pore channel orientation. Bending strength was determined in a coaxial double ring test resulting in a maximum bending strength of ~2 MPa.

The cryptogenic marine red alga Chondria tumulosa was first observed in 2016 in subtidal habitats at Manawai (Pearl and Hermes Atoll) in the Papahānaumokuākea Marine National Monument (PMNM), Hawai‘i. Without molecular or morphological matches to any known species, it was described in 2020 and declared cryptogenic. This alga has substantially increased in benthic cover and has been discovered on two additional atolls in PMNM: Kuaihelani (Midway) and Hōlanikū (Kure). It exhibits several characteristics indicative of non-native origins including putative prior absence in the region, persistence in high densities over nearly a decade, apparent lack of native herbivore pressure, and strong tetrasporophytic bias. Importantly, it is negatively impacting the culturally and ecologically valuable reefs of PMNM. The geographical origin of this putative invasion is unknown, and there are no published reports of the species occurring anywhere other than PMNM. The central Pacific location of Hawai‘i allows a broad range of potential sources for the origin of C. tumulosa . Taxonomic ambiguities within the genus Chondria and challenges associated with sampling necessitate the development of a narrowed set of search locations and efficient search strategies to detect the species outside of PMNM. Attachment to floating debris is a potential introduction vector for C. tumulosa into PMNM, and an oceanographic model was used to identify the most likely source locations for this pathway between 2000 and 2015, including Japan in the western Pacific, Johnston Atoll, the Line Islands including Palmyra Atoll in the central Pacific, and Clipperton Atoll and the Galápagos Islands in the eastern Pacific. We used a recently developed and validated eDNA assay for detecting C. tumulosa from three of the regions of interest to screen for C. tumulosa with no samples yielding positive detections. We provide a framework for investigating positive eDNA field detections using in-water surveys, microscopy, and DNA barcoding. A parallel sampling effort targeting preserved specimens stored in global herbaria is also presented, which did not yield any detections. Several Chondria species remain targets for sequencing from global herbaria. Identification of the native range of C. tumulosa is a critical step that will allow for an evaluation of its evolutionary ecology and any shifts that may have occurred that facilitated its putative invasion and subsequent spread, offering insights crucial for the development of mitigation strategies to safeguard PMNM against further risk.