Oncostatin M Promotes Mammary Tumor Metastasis to Bone and Osteolytic Bone Degradation

Oncostatin M (OSM) is an interleukin-6 (IL-6) family cytokine that has been implicated in a number of biological processes including inflammation, hematopoiesis, immune responses, development, and bone homeostasis. Recent evidence suggests that OSM may promote breast tumor invasion and metastasis. We investigated the role of OSM in the formation of bone metastases in vivo using the 4T1.2 mouse mammary tumor model in which OSM expression was knocked down using shRNA (4T1.2-OSM). 4T1.2-OSM cells were injected orthotopically into Balb/c mice, resulting in a greater than 97% decrease in spontaneous metastasis to bone compared to control cells. Intratibial injection of these same 4T1.2-OSM cells also dramatically reduced the osteolytic destruction of trabecular bone volume compared to control cells. Furthermore, in a tumor resection model, mice bearing 4T1.2-OSM tumors showed an increase in survival by a median of 10 days. To investigate the specific cellular mechanisms important for OSM-induced osteolytic metastasis to bone, an in vitro model was developed using the RAW 264.7 preosteoclast cell line co-cultured with 4T1.2 mouse mammary tumor cells. Treatment of co-cultures with OSM resulted in a 3-fold induction of osteoclastogenesis using the TRAP assay. We identified several tumor cell–induced factors including vascular endothelial growth factor, IL-6, and a previously uncharacterized OSM-regulated bone metastasis factor, amphiregulin (AREG), which increased osteoclast differentiation by 4.5-fold. In addition, pretreatment of co-cultures with an anti-AREG neutralizing antibody completely reversed OSM-induced osteoclastogenesis. Our results suggest that one mechanism for OSM-induced osteoclast differentiation is via an AREG autocrine loop, resulting in decreased osteoprotegerin secretion by the 4T1.2 cells. These data provide evidence that OSM might be an important therapeutic target for the prevention of breast cancer metastasis to bone

Searching for Intragroup Light in Deep U-band Imaging of the COSMOS Field

We present the results of deep, ground based U-band imaging with the Large Binocular Telescope of the Cosmic Evolution Survey (COSMOS) field as part of the near-UV imaging program, UVCANDELS. We utilize a seeing sorted stacking method along with night-to-night relative transparency corrections to create optimal depth and optimal resolution mosaics in the U-band, which are capable of reaching point source magnitudes of AB 26.5 mag at 3 sigma. These ground based mosaics bridge the wavelength gap between the HST WFC3 F27W and ACS F435W images and are necessary to understand galaxy assembly in the last 9-10 Gyr. We use the depth of these mosaics to search for the presence of U-band intragroup light (IGrL) beyond the local Universe. Regardless of how groups are scaled and stacked, we do not detect any U-band IGrL to unprecedented U-band depths of 29.1-29.6 mag/arcsec2, which corresponds to an IGrL fraction of less than 1% of the total group light. This stringent upper limit suggests that IGrL does not contribute significantly to the Extragalactic Background Light at short wavelengths. Furthermore, the lack of UV IGrL observed in these stacks suggests that the atomic gas observed in the intragroup medium (IGrM) is likely not dense enough to trigger star formation on large scales. Future studies may detect IGrL by creating similar stacks at longer wavelengths or by pre-selecting groups which are older and/or more dynamically evolved similar to past IGrL observations of compact groups and loose groups with signs of gravitational interactions.Comment: Accepted to PAS

The Lyman Continuum Escape Fraction of Star-forming Galaxies at 2.4≲z≲3.72.4\lesssim z\lesssim3.7 from UVCANDELS

The UltraViolet Imaging of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey Fields (UVCANDELS) survey is a Hubble Space Telescope (HST) Cycle-26 Treasury Program, allocated in total 164 orbits of primary Wide-Field Camera 3 Ultraviolet and Visible light F275W imaging with coordinated parallel Advanced Camera for Surveys F435W imaging, on four of the five premier extragalactic survey fields: GOODS-N, GOODS-S, EGS, and COSMOS. We introduce this survey by presenting a thorough search for galaxies at $z\gtrsim2.4$ that leak significant Lyman continuum (LyC) radiation, as well as a stringent constraint on the LyC escape fraction ($f_{\rm esc}$) from stacking the UV images of a population of star-forming galaxies with secure redshifts. Our extensive search for LyC emission and stacking analysis benefit from the catalogs of high-quality spectroscopic redshifts compiled from archival ground-based data and HST slitless spectroscopy, carefully vetted by dedicated visual inspection efforts. We report a sample of five galaxies as individual LyC leaker candidates, showing $f_{\rm esc}^{\rm rel}\gtrsim60\%$ estimated using detailed Monte Carlo analysis of intergalactic medium attenuation. We develop a robust stacking method to apply to five samples of in total 85 non-detection galaxies in the redshift range of $z\in[2.4,3.7]$. Most stacks give tight 2-$\sigma$ upper limits below $f_{\rm esc}^{\rm rel}<6\%$. A stack for a subset of 32 emission-line galaxies shows tentative LyC leakage detected at 2.9-$\sigma$, indicating $f_{\rm esc}^{\rm rel}=5.7\%$ at $z\sim2.65$, supporting the key role of such galaxies in contributing to the cosmic reionization and maintaining the UV ionization background. These new F275W and F435W imaging mosaics from UVCANDELS have been made publicly available on the Barbara A. Mikulski Archive for Space Telescopes.Comment: 33 pages, 21 figures, and 5 tables. Resubmitted after addressing the referee repor

Development of Bioluminescent Mammary Cancer Cells with Knocked Down Expression of OSM for Detection of Bone Metastasis \u3cem\u3ein Vivo\u3c/em\u3e

Oncostatin M (OSM) is a multifunctional cytokine belonging to the interleukin (IL)-6 subfamily. OSM was originally recognized by its ability to decrease breast and other tumor cell proliferation in vitro. Based on data from our lab, we hypothesize that OSM is a mediator of breast cancer metastasis to bone. For our model system, we are utilizing two cell lines, 4T1.2 and 66c14, which were derived from the mammary carcinoma of a Balb/c mouse. 4T1.2 cells express medium levels of OSM and are highly metastatic to bone, lymph nodes, and lungs when injected into the mammary fat pad of Balb/c mice. 66c14 cells express low levels of OSM and demonstrate low levels of metastasis that is restricted to the lymph nodes and lungs. A small hairpin RNA (shRNA) to OSM was designed and stably transfected into the cells in order to decrease or ‘knock down’ OSM expression. Enzyme-linked immunosorbent assay (ELISA) was used to quantify levels of secreted OSM protein in both cell lines and confirm knocked down OSM expression. Normal 4T1.2 and 66c14 cells, as well as knockdown 4T1.2 and 66c14 cells, will be injected into the mammary fat pad of female Balb/c mice. To visualize metastasis to bone in vivo, the cell lines are currently being transfected with pGL4, a vector containing a bioluminescence maker called luciferase. The luciferase gene was isolated from the firefly and encodes an enzyme, which along with its substrate luciferin, can be used to image the cells expressing luciferase in vivo. Our aim is to determine whether tumor cell-produced OSM is necessary for breast cancer metastasis to bone by measuring metastasis in cells that have knocked down expression of OSM. If our results confirm our hypothesis, inhibiting OSM and its signaling may be a new target for treating breast cancer metastasis to bone

Ultraviolet and Blue Optical Imaging of UVCANDELS

The UltraViolet Imaging of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey Fields (UVCANDELS) survey provided ultraviolet F275W imaging with coordinated parallel optical F435W imaging in four of the five CANDELS fields: GOODS-N, GOODS-S, EGS, and COSMOS, covering a total area of ∼426 arcmin2. UVCANDELS takes primary WFC3/UVIS F275W exposures at a uniform 3-orbit depth and ACS F435W exposures (in parallel) at slightly varying depth due to the roll angle constraints and the overlap from the increased field of view of the ACS camera, reaching a limiting magnitude of ∼27 and ∼28 ABmag (5σ in 0.″2 apertures) for F275W and F435W, respectively. We present the results of the UVCANDELS observations, custom calibrations, and the creation of F275W and F435W imaging mosaics, which have been made publicly available on the Barbara A. Mikulski Archive for Space Telescopes

JWST PEARLS. Prime Extragalactic Areas for Reionization and Lensing Science: Project Overview and First Results

We give an overview and describe the rationale, methods, and first results from NIRCam images of the JWST “Prime Extragalactic Areas for Reionization and Lensing Science” (PEARLS) project. PEARLS uses up to eight NIRCam filters to survey several prime extragalactic survey areas: two fields at the North Ecliptic Pole (NEP); seven gravitationally lensing clusters; two high redshift protoclusters; and the iconic backlit VV 191 galaxy system to map its dust attenuation. PEARLS also includes NIRISS spectra for one of the NEP fields and NIRSpec spectra of two high-redshift quasars. The main goal of PEARLS is to study the epoch of galaxy assembly, active galactic nucleus (AGN) growth, and First Light. Five fields—the JWST NEP Time-Domain Field (TDF), IRAC Dark Field, and three lensing clusters—will be observed in up to four epochs over a year. The cadence and sensitivity of the imaging data are ideally suited to find faint variable objects such as weak AGN, high-redshift supernovae, and cluster caustic transits. Both NEP fields have sightlines through our Galaxy, providing significant numbers of very faint brown dwarfs whose proper motions can be studied. Observations from the first spoke in the NEP TDF are public. This paper presents our first PEARLS observations, their NIRCam data reduction and analysis, our first object catalogs, the 0.9-4.5 μm galaxy counts and Integrated Galaxy Light. We assess the JWST sky brightness in 13 NIRCam filters, yielding our first constraints to diffuse light at 0.9-4.5 μm. PEARLS is designed to be of lasting benefit to the community

JWST PEARLS. Prime Extragalactic Areas for Reionization and Lensing Science: Project Overview and First Results

We give an overview and describe the rationale, methods, and first results from NIRCam images of the JWST “Prime Extragalactic Areas for Reionization and Lensing Science” (PEARLS) project. PEARLS uses up to eight NIRCam filters to survey several prime extragalactic survey areas: two fields at the North Ecliptic Pole (NEP); seven gravitationally lensing clusters; two high redshift protoclusters; and the iconic backlit VV 191 galaxy system to map its dust attenuation. PEARLS also includes NIRISS spectra for one of the NEP fields and NIRSpec spectra of two high-redshift quasars. The main goal of PEARLS is to study the epoch of galaxy assembly, active galactic nucleus (AGN) growth, and First Light. Five fields—the JWST NEP Time-Domain Field (TDF), IRAC Dark Field, and three lensing clusters—will be observed in up to four epochs over a year. The cadence and sensitivity of the imaging data are ideally suited to find faint variable objects such as weak AGN, high-redshift supernovae, and cluster caustic transits. Both NEP fields have sightlines through our Galaxy, providing significant numbers of very faint brown dwarfs whose proper motions can be studied. Observations from the first spoke in the NEP TDF are public. This paper presents our first PEARLS observations, their NIRCam data reduction and analysis, our first object catalogs, the 0.9-4.5 μm galaxy counts and Integrated Galaxy Light. We assess the JWST sky brightness in 13 NIRCam filters, yielding our first constraints to diffuse light at 0.9-4.5 μm. PEARLS is designed to be of lasting benefit to the community