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Supernumerary centrosomes and increased MT growth rates are associated with...
Published: 18 May 2022
FIGURE 1. Supernumerary centrosomes and increased MT growth rates are associated with invasiveness of melanoma cells. A, 3D invasion of melanoma cell lines. Spheroids of the indicated melanoma cell lines were embedded into Matrigel and 3D invasion was followed for 48 hours. Left: Representative images of spheroids and invaded cells. Scale bar, 50 μm. Right: Measurements of the spheroid outgrowth area after 48 hours in Matrigel (mean ± SD, n = 19–23 spheroids, t test). B, Live-cell measurements of MT plus end growth rates in melanoma cells during interphase. Left: Example image of a melanoma cell expressing EB3-GFP and used for measurements of MT growth rates by live-cell microscopy. Right: Determination of MT growth rates in the indicated melanoma cell lines. Scatter dot plots showing average MT growth rates (20 MTs/cell, n = 30 cells, mean ± SD, t test). C, Detection of supernumerary centrosomes in invasive and noninvasive melanoma cells. Top: Representative immunofluorescence microscopy images of melanoma cells with or without supernumerary (>2) centrosomes and analyzed by detecting γ-tubulin as a marker for centrosomes. White triangles mark centrosomes, nuclei were stained by Hoechst. Scale bar, 5 μm. Bottom: Quantification of the proportion of cells with supernumerary centrosomes (mean ± SD, n = 600 cells, t test). D, Representative Western blots detecting PLK4 or STIL overexpression in noninvasive melanoma cells. α-tubulin was detected as a loading control. E, Quantification of the proportion of noninvasive melanoma cells with supernumerary centrosomes upon STIL or PLK4 overexpression. Top: example images of SK-Mel-173 cells with or without STIL or PLK4 overexpression. Centrosomes were stained by anti-γ-tubulin antibodies and nuclei were stained by Hoechst. Scale bar, 5 μm. Bottom: The graph shows the proportion of cells with supernumerary centrosomes (mean ± SD, n = 300 cells, t test). F, Determination of MT plus end growth rates in the indicated noninvasive melanoma cells after PLK4 or STIL overexpression. Scatter dot plots showing average MT growth rates (20 MTs/cell, n = 30 cells, mean ± SD, t test). More
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Supernumerary centrosomes cause increased MT growth rates to promote melano...
Published: 18 May 2022
FIGURE 2. Supernumerary centrosomes cause increased MT growth rates to promote melanoma cell invasion. A, Representative Western blots showing siRNA mediated downregulation of ch-TOG in the indicated invasive melanoma cells. α-tubulin was detected as a protein loading control. B, Determination of MT plus end growth rates in invasive melanoma cell lines after partial siRNA-mediated depletion of ch-TOG. Scatter dot plots show average MT growth rates (20 MTs/cell, mean ± SD, n = 30, t test). C, Measurements of MT growth rates in invasive melanoma cell lines after treatment with DMSO (control) or 0.5 nmol/L Taxol for 16 hours. Noninvasive SK-Mel-173 cells were used as control. Scatter dot plots show average MT growth rates (20 MTs/cell, mean ± SD, n = 30, t test). D, Quantification of the proportion of invasive melanoma cells with supernumerary centrosomes upon partial depletion of ch-TOG or after treatment with Taxol (mean ± SD, n = 300 cells, t-test). E, Invasive 3D outgrowth of spheroids derived from invasive SK-Mel-103 melanoma cells and treated with 0.5 nmol/L Taxol or after siRNA-mediated depletion of ch-TOG. Spheroids were embedded into Matrigel and 3D outgrowth was followed for 48 hours in the presence or absence of treatments. Top: representative microscopy images showing outgrowth of 3D spheroids derived from SK-Mel-103 and SK-Mel-147 cells. Scale bar, 50 μm. Bottom: Quantification of the 3D outgrowth area of spheroids derived from the indicated invasive melanoma cells after treatment with DMSO (control), 0.5 nmol/L Taxol or upon siRNA-mediated knockdown of CKAP5 after 48 hours (mean ± SD, n = 18–26 spheroids, t test). More
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Induction of increased MT growth activity by paracrine signaling.  A,  Mode...
Published: 18 May 2022
FIGURE 3. Induction of increased MT growth activity by paracrine signaling. A, Model depicting the paracrine induction of increased MT growth rates. B, Measurements of MT growth rates in noninvasive SK-Mel-173 cells after cocultivation of noninvasive or invasive melanoma cells for 24 hours. C, Measurements of MT growth rates in the indicated noninvasive melanoma cells after treatment with CM derived from noninvasive or invasive cells for 16 hours. D, Measurements of MT growth rates in the indicated noninvasive melanoma cells after treatment with conditioned media derived from the same cells with or without PLK4 or STIL overexpression. E, Measurements of MT growth rates in noninvasive melanoma cells after treatment with conditioned media derived from the indicated invasive melanoma cells with or without partial depletion of ch-TOG (CKAP5 repression). F, Measurements of MT growth rates in noninvasive SK-Mel-173 cells after treatment with conditioned media derived from the same cells with PLK4 overexpression and concomitant CKAP5 repression. G, Measurements of MT growth rates in noninvasive SK-Mel-173 cells after treatment with conditioned media derived from the same cells with or without CKAP5 overexpression. All scatter dot plots show average MT growth rates (20 MTs/cell, mean ± SD, n = 30, t test). More
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MVs mediate increased MT growth rates.  A,  Measurements of MT growth rates...
Published: 18 May 2022
FIGURE 4. MVs mediate increased MT growth rates. A, Measurements of MT growth rates in noninvasive melanoma cells after treatment with CM derived from noninvasive or invasive cells before and after centrifugation to deplete MVs from the media. B, Measurements of MT growth rates in noninvasive melanoma cells after treatment with conditioned media derived from noninvasive or invasive cells before and after heating the media for 30 minutes at 56°C to denature proteins. All scatter dot plots show average MT growth rates (20 MTs/cell, mean ± SD, n = 30, t test). More
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MVs comprising HER2 mediate enhanced MT growth.  A,  Identification of HER2...
Published: 18 May 2022
FIGURE 5. MVs comprising HER2 mediate enhanced MT growth. A, Identification of HER2/ERBB2 as a constituent of MVs upon induction of supernumerary centrosomes. Isolated MVs derived from noninvasive SK-Mel-173 cells with or without overexpression of PLK4 were subjected to MS analysis. The volcano plot depicts HER2/ERBB2 and HER3/ERBB3 as well as several marker proteins for MVs. B, Detection of HER2 in whole-cell lysates and in MVs derived from noninvasive SK-Mel-173 cells with or without PLK4 overexpression. Representative Western blots detecting HER2, PLK4, GAPDH (loading control for MVs) and α-tubulin (loading control for whole-cell lysates) are shown. C, Representative Western blots showing mild overexpression of HER2 in noninvasive SK-Mel-173 cells. β-actin was detected as a loading control. D, Measurements of MT growth rates in noninvasive melanoma cells after mild overexpression of HER2 in the absence or presence of the irreversible HER2 kinase inhibitor canertinib. Scatter dot plots show average MT growth rates (20 MTs/cell, mean ± SD, n = 30, t test). E, Measurements of MT growth rates in the indicated invasive melanoma cells after treatment with DMSO (control) or the HER2 inhibitor trastuzumab. The scatter dot plots show average MT growth rates (20 MTs/cell, mean ± SD, n = 30, t test). F, 3D outgrowth of spheroids derived from invasive melanoma cells and treated with DMSO (control) or with the HER2 inhibitor canertinib. Left: Representative example images. Scale bar, 25 μm. Right: Quantification of the 3D outgrowth area of spheroids derived from the indicated invasive melanoma cells in the absence or presence of canertinib. The bar graphs show mean values ± SD (n = 19–27 spheroids, t test). G, Measurements of MT growth rates in noninvasive melanoma cells (SK-Mel-173) after treatment with MVs derived from noninvasive (SK-Mel-173) or invasive cells (SK-Mel-147 or SK-Mel-103) that were transiently treated with reversible (trastuzumab) or irreversible (canertinib) HER2 inhibitor. The scatter dot plots show average MT growth rates (20 MTs/cell, mean ± SD, n = 30, t test). More
Journal Articles
Journal Articles
Journal Articles
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Selinexor induces growth inhibition in KRAS G12C inhibitor–resistant cancer...
Published: 10 May 2022
FIGURE 1 Selinexor induces growth inhibition in KRAS G12C inhibitor–resistant cancer cells. A, KRAS G12C–mutant MiaPaCa-2 cells exposed to incremental doses of AMG510 and MRTX1257 in long-term cell culture, eventually developed drug-resistance as shown by their unresponsiveness to drug treatment in MTT assay and several fold increase in the drug IC50 values compared with parental cells. B, AMG510- and MRTX1257-resistant MiaPaCa-2 cell lines show sensitivity toward selinexor induced growth inhibition. Parental as well as resistant cells were treated with selinexor for 72 hours and MTT assay was performed as described in Methods. All results are expressed as percentage of control ± SEM of six replicates. More
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Selinexor and MRTX1257 show synergistic effects on the inhibition of cell p...
Published: 10 May 2022
FIGURE 2 Selinexor and MRTX1257 show synergistic effects on the inhibition of cell proliferation in vitro. NCI-H2122 ( A ), NCI-H358 ( B ), and MiaPaCa-2 ( C ) cells were exposed to the indicated concentrations of either selinexor, MRTX1257, or a combination of both for 72 hours, and cell proliferation was evaluated by MTT assay as described in Materials and Methods. CalcuSyn software was employed to generate isobolograms and determine CI values from the resulting data. CI < 1 indicates synergistic effect of the drug combination at the corresponding doses. All results are expressed as percentage of control ± SEM of six replicates. More
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Selinexor in combination with MRTX1257 or AMG510 suppresses spheroid format...
Published: 10 May 2022
FIGURE 3 Selinexor in combination with MRTX1257 or AMG510 suppresses spheroid formation as well as significantly reduces the number of spheroids in 3D cultures of KRAS G12C–mutant cancer cells. MiaPaCa-2 ( A ) and NCI-H2122 ( B ) cells were seeded in ultra-low attachment plates and treated with in... More
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Combinations of selinexor with various KRAS G12C inhibitors inhibit the abi...
Published: 10 May 2022
FIGURE 4 Combinations of selinexor with various KRAS G12C inhibitors inhibit the ability of KRAS G12C–mutant cancer cells to form colonies. MiaPaCa-2 cells were plated in 6-well plates (500 cells per well) and treated with combinations of selinexor with MRTX1257 ( A ), MRTX849 ( B ), and AMG510 ( ... More
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KRAS G12C inhibitors in combination with selinexor inhibit cell growth sign...
Published: 10 May 2022
FIGURE 5 KRAS G12C inhibitors in combination with selinexor inhibit cell growth signaling and prevent cell-cycle progression. ( A ) Immunoblots showing suppression of P70 S6 Kinase and ERK activation in NCI-H358 and MiaPaCa-2 cells treated with MRTX1257, AMG510 and MRTX849 as single agents (300 nm... More
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Preclinical antitumor efficacy of selinexor and KRAS G12C inhibitor combina...
Published: 10 May 2022
FIGURE 6 Preclinical antitumor efficacy of selinexor and KRAS G12C inhibitor combination in KRAS G12C CDX model. MiaPaCa-2 tumor xenografts were transplanted unilaterally in ICR-SCID mice, and the mice were randomly divided into four groups. Drug treatment was started one week after implanting xenografts when the average tumor volume reached 166 mm3. Selinexor was administered once a week at 15 mg/kg, while AMG510 was given daily at 100 mg/kg for 3 weeks. Tumor volume ( A ) and animal survival ( B ) were monitored up to 150 days posttransplantation. Residual tumor tissues from each group were used for measuring mRNA levels of KRAS, XPO1, ERK2 and BCL-2 ( C ), and performing IHC staining for Ki67, KRAS, and cleaved caspase-3 ( D ). PO, orally; QD, every day. More
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Tumor purity by passage in PDX models.  A,  Median VAF in PDX models by pas...
Published: 10 May 2022
FIGURE 1 Tumor purity by passage in PDX models. A, Median VAF in PDX models by passage. A total of 1,608 PDX models spread into 11 passages. No significant difference was found across passages based on one-way ANOVA. B, Tumor purity in the human cells of PDX models by passage. C, A strong co... More
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Tumor purity in PDX models depends on mouse strain.  A,  Tumor purity is hi...
Published: 10 May 2022
FIGURE 2 Tumor purity in PDX models depends on mouse strain. A, Tumor purity is higher in NOD/SCID than BALB/c nude mice. Tumor purity was calculated using a set of 630 tumor samples in nine cancers in both strains. P value is from Mann–Whitney U test. B, Tumor purity comparison by mouse strain for nine cancers. P values are from Mann–Whitney U test. C, Tumor purity is positively correlated between NOD/SCID and BALB/c nude mice for nine cancers. CR, colorectal; ES, esophageal; GA, gastric; HN, head and neck; LI, liver; LU, lung; OV, ovarian; PA, pancreatic; SA, sarcoma. More
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Tumor purity in PDX models is cancer specific and correlates with patient c...
Published: 10 May 2022
FIGURE 3 Tumor purity in PDX models is cancer specific and correlates with patient cancers. A, Tumor purity in 27 cancers estimated from a deep NGS assay. Hematoxylin and eosin (H&E) staining of PDX tumors in two cancers with low tumor purity: pancreatic ductal adenocarcinoma ( B ) and clear-cell renal cell carcinoma ( C ), and two cancers with high tumor purity: gastrointestinal stromal tumor ( D ) and melanoma ( E ). F and G, Tumor purity is positively correlated between PDX tumors and TCGA patient tumors. TCGA tumor purity was inferred by the ABSOLUTE method based on somatic DNA alternations ( F , data from ref. 25 ), or by the ESTIMATE method based on gene expression ( G , data from ref. 38 ). Cancer abbreviations: AL, acute lymphoblastic leukemia; AM, acute myeloid leukemia; BL, bladder; BN, brain; BR, breast; CC, cholangiocarcinoma; CR, colorectal; CV, cervical; ES, esophageal; FT, fallopian tube carcinoma; GA, gastric; GL, gallbladder; GS, gastrointestinal stromal tumor; HN, head and neck; KI, kidney; NSCLC, non–small cell lung cancer; LI, liver; LY, lymphoma; ME, melanoma; MU, mixed Mullerian cancer; OV, ovarian; PA, pancreatic; PE, peritoneal; PR, prostate; SA, sarcoma; SCLC, small- cell lung cancer; UT, uterine. More
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Estimating PDX tumor purity from NGS data. In 157 NOD/SCID PDX tumors, the ...
Published: 10 May 2022
FIGURE 4 Estimating PDX tumor purity from NGS data. In 157 NOD/SCID PDX tumors, the correlation between the ground truth tumor purities estimated by a deep NGS assay and tumor purities estimated by counting human and mouse reads in WES ( A ) and RNA-seq data ( B ), the former shows a strong nonlin... More