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  • American Association for Cancer Research (AACR)  (5)
  • Gaczynska, Maria E.  (5)
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  • American Association for Cancer Research (AACR)  (5)
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  • 1
    Online Resource
    Online Resource
    Adipokines Deregulate Cellular Communication via Epigenetic Repression of Gap Junction Loci in Obese Endometrial Cancer
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 1 ( 2019-01-01), p. 196-208
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 1 ( 2019-01-01), p. 196-208
    Abstract: Emerging evidence indicates that adipose stromal cells (ASC) are recruited to enhance cancer development. In this study, we examined the role these adipocyte progenitors play relating to intercellular communication in obesity-associated endometrial cancer. This is particularly relevant given that gap junctions have been implicated in tumor suppression. Examining the effects of ASCs on the transcriptome of endometrial epithelial cells (EEC) in an in vitro coculture system revealed transcriptional repression of GJA1 (encoding the gap junction protein Cx43) and other genes related to intercellular communication. This repression was recapitulated in an obesity mouse model of endometrial cancer. Furthermore, inhibition of plasminogen activator inhibitor 1 (PAI-1), which was the most abundant ASC adipokine, led to reversal of cellular distribution associated with the GJA1 repression profile, suggesting that PAI-1 may mediate actions of ASC on transcriptional regulation in EEC. In an endometrial cancer cohort (n = 141), DNA hypermethylation of GJA1 and related loci TJP2 and PRKCA was observed in primary endometrial endometrioid tumors and was associated with obesity. Pharmacologic reversal of DNA methylation enhanced gap-junction intercellular communication and cell–cell interactions in vitro. Restoring Cx43 expression in endometrial cancer cells reduced cellular migration; conversely, depletion of Cx43 increased cell migration in immortalized normal EEC. Our data suggest that persistent repression by ASC adipokines leads to promoter hypermethylation of GJA1 and related genes in the endometrium, triggering long-term silencing of these loci in endometrial tumors of obese patients. Significance: Studies reveal that adipose-derived stem cells in endometrial cancer pathogenesis influence epigenetic repression of gap junction loci, which suggests targeting of gap junction activity as a preventive strategy for obesity-associated endometrial cancer.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-18-1615
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Single-Cell Proteomic Profiling Identifies Combined AXL and JAK1 Inhibition as a Novel Therapeutic Strategy for Lung Cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 7 ( 2020-04-01), p. 1551-1563
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 7 ( 2020-04-01), p. 1551-1563
    Abstract: Cytometry by time-of-flight (CyTOF) simultaneously measures multiple cellular proteins at the single-cell level and is used to assess intertumor and intratumor heterogeneity. This approach may be used to investigate the variability of individual tumor responses to treatments. Herein, we stratified lung tumor subpopulations based on AXL signaling as a potential targeting strategy. Integrative transcriptome analyses were used to investigate how TP-0903, an AXL kinase inhibitor, influences redundant oncogenic pathways in metastatic lung cancer cells. CyTOF profiling revealed that AXL inhibition suppressed SMAD4/TGFβ signaling and induced JAK1–STAT3 signaling to compensate for the loss of AXL. Interestingly, high JAK1–STAT3 was associated with increased levels of AXL in treatment-naïve tumors. Tumors with high AXL, TGFβ, and JAK1 signaling concomitantly displayed CD133-mediated cancer stemness and hybrid epithelial-to-mesenchymal transition features in advanced-stage patients, suggesting greater potential for distant dissemination. Diffusion pseudotime analysis revealed cell-fate trajectories among four different categories that were linked to clinicopathologic features for each patient. Patient-derived organoids (PDO) obtained from tumors with high AXL and JAK1 were sensitive to TP-0903 and ruxolitinib (JAK inhibitor) treatments, supporting the CyTOF findings. This study shows that single-cell proteomic profiling of treatment-naïve lung tumors, coupled with ex vivo testing of PDOs, identifies continuous AXL, TGFβ, and JAK1–STAT3 signal activation in select tumors that may be targeted by combined AXL–JAK1 inhibition. Significance: Single-cell proteomic profiling of clinical samples may facilitate the optimal selection of novel drug targets, interpretation of early-phase clinical trial data, and development of predictive biomarkers valuable for patient stratification.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-19-3183
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Abstract 2766: Amplification-associated upregulation of genes involved in oxidative phosphorylation for disseminated prostate cancer cells
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2766-2766
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2766-2766
    Abstract: Purpose: Little is known about adaptive selection of tumor cells transiting from in situ proliferation to distant colonization through blood circulation. This study used genomic, transcriptomic, and biophysical analyses at single-cell levels to explore biological and physical properties of circulating tumor cells (CTCs) undergoing hemodynamic stress. The aims are trying to understand how CTCs strive to survive in the bloodstream and to develop strategies for therapeutic intervention. Experimental Design: We compared genomic profiles of CTCs in blood and primary tumor cells shed in urine of prostate cancer patients to identify amplified regions preferentially retained in CTCs. Single-cell RNA-seq was used to confirm amplification-associated overexpression of genes in CTCs. Results: Among 261 recurrently amplified genomic regions in the analysis, 70 were found predominantly shown in CTCs relative to primary tumor cells. In line with the results at the genomic level, the transcriptomic data of CTCs demonstrate a great amount of cells showing high expression levels in the oxidative phosphorylation (OXPHOS) pathway compared to other hallmark gene sets. The finding suggests that tumor cells with these pre-existing genomic alterations were adaptively selected for transcription reprogramming during blood circulation. Specifically, amplified genes associated with OXPHOS were exploited by CTCs for alternative fuels. As to the upstream of this transcription event, we found the expression of MEN1, encoding menin known to form a transcription factor complex with the mixed-lineage leukemia protein (MLL) in prostate cancer cells, was positively correlated with 11 of the 14 OXPHOS loci in the Cancer Genomic Atlas prostate cancer cohort. In vitro assay showed that MEN1 knockdown by shRNA resulted in attenuation of both mRNA and protein expression of OXPHOS loci in PC-3 cells. Taken together pre-existing amplification of OXPHOS loci can be used as a transcription apparatus by menin for metabolic reprogramming of tumor cells in response to harsh microenvironments in the bloodstream. Conclusions: Single-cell profiling identified signaling pathways that are crucial for CTCs to survive in the bloodstream. The finding suggests that a metabolic shift from Warburg to OXPHOS metabolism can be associated with a hybrid mesenchymal-epithelial phenotype of CTCs. Moreover, the study demonstrates the feasibility of routinely conducting single-cell analysis of exfoliated tumor cells for minimally invasive monitoring of disease progression and treatment response in prostate cancer patients Citation Format: Chun-Lin Lin, Tan Xi, Chia-Nung Hung, Pawel A. Osmulski, Chih-Wei Chou, Meizhen Chen, Chiou-Miin Wang, Kohzoh Mitsuya, Nameer Kirma, Maria E. Gaczynska, Chun-Liang Chen, Tim H.-M. Huang. Amplification-associated upregulation of genes involved in oxidative phosphorylation for disseminated prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2766.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2766
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 4
    Online Resource
    Online Resource
    Abstract 2193: AXL inhibitor TP-0903 attenuates AXL-TGFbeta Hippo signaling axis in lung adenocarcinoma cells
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2193-2193
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2193-2193
    Abstract: Background: Non-small cell lung cancer (NSCLC) is a molecularly heterogeneous disease with a high propensity for drug resistance and metastasis. AXL, a member of the Tyro3-AXL-Mer family of receptor tyrosine kinases, is a central regulator of epithelial-to-mesenchymal transition (EMT) and enables tumor cells to invade and acquire drug resistance. AXL is overexpressed in lung tumors, correlates positively with tumor invasion, drug resistance, and negatively predicts overall survival. We mechanistically interrogate the effects of AXL inhibitor TP-0903 on EMT in lung adenocarcinoma cells using transcriptomic and proteomic profiling. Methods: Atomic force microscopy, Western blot analysis, RNA sequencing and mass cytometry (CyTOF) were all used to scrutinize the biomechanical properties, phenotypic, transcriptomic and proteomic profiles of A549 cells treated with 40nM TP0903 or shAXL knockdown. Results: TP-0903 attenuates total AXL/AXL phosphorylation and blunts transcriptional responses to TGFβ-Hippo signaling by disrupting the transcriptional complexes formed by SMAD2/3, SMAD4, YAP1 and TAZ. AXL knockdown or TP-0903 reverses EMT phenotype and reduces migration potential in A549 and H2009 adenocarcinoma cell lines. CyTOF data also identified resistant clones that overexpress TGFβ receptor II, TAZ protein and display hybrid EMT phenotypes. Conclusions: We are the first to report the interplay between AXL and TGFβ-Hippo signaling axis. TP-0903 study agent has excellent therapeutic promise in NSCLC and we speculate that TP-0903 drug can target epithelial to mesenchymal transitional states in lung cancer cells possibly through the inhibition of the AXL-TGFβ-Hippo signaling axis. Citation Format: Josephine Amalia Taverna, Chia-Nung Hung, Chun-Lin Lin, Pawel Osmulski, Meizhen Chen, Chiou-Miin Wang, Nicholas L. L. Lucio, Nameer Kirma, Chih-Wei Chou, Maria E. Gaczynska, Alia Nazarullah, Mark Wade, Lars Mouritsen, Tim Huang. AXL inhibitor TP-0903 attenuates AXL-TGFbeta Hippo signaling axis in lung adenocarcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2193.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2193
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 5
    Online Resource
    Online Resource
    Abstract B29: AXL Inhibitor TP-0903 attenuates TGFβ-Hippo signaling in lung adenocarcinoma cells
    American Association for Cancer Research (AACR) ; 2020
    In:  Molecular Cancer Research Vol. 18, No. 8_Supplement ( 2020-08-01), p. B29-B29
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 8_Supplement ( 2020-08-01), p. B29-B29
    Abstract: Background: Non-small cell lung cancer (NSCLC) is a molecularly heterogeneous disease with a high propensity for drug resistance and metastasis. AXL, a member of the Tyro3-AXL-Mer (TAM) family of receptor tyrosine kinases, is a central regulator of epithelial-to-mesenchymal transition (EMT) and enables tumor cells to invade and acquire drug resistance. AXL is overexpressed in NSCLC and its expression correlates positively with tumor invasion, drug resistance, and negatively predicts overall survival. We mechanistically interrogated the effects of the AXL inhibitor, TP-0903, on EMT in NSCLC cells using transcriptomic and proteomic profiling. Methods: Atomic force microscopy, Western blot analysis, RNA sequencing, and mass cytometry (CyTOF) were used to evaluate the phenotypic, transcriptomic, and proteomic profiles of A549 cells treated with 40 nM TP-0903 or shAXL knockdown. A549 and H1650 NSCLC xenograft models were used to explore the consequences of AXL inhibition in vivo. Results: As expected, TP-0903 treatment attenuated AXL signaling and downstream phosphorylation in the A549 cells. Interestingly, the treatment also reduced gene expression responses to TGFβ-Hippo signaling by disrupting the transcriptional complexes formed by SMAD2/3, SMAD4, YAP1, and TAZ. Consistent with AXL inhibition, TP-0903 reversed the mesenchymal phenotype in A549 and H2009 cell lines and decreased their migratory potential in culture. The CyTOF analysis on TP-0903-treated cells identified resistant clones overexpressing TGFβ receptor II (TGFBR2) and TAZ proteins and displaying hybrid EMT phenotypes. TP-0903 was also active in suppressing A549 or H1650 tumor growth in vivo. Conclusions: We are the first to report the interplay between AXL and TGFβ-Hippo signaling axis. TP-0903 has excellent therapeutic promise in NSCLC and we speculate that TP-0903 can target mesenchymal transitional states in NSCLC, possibly through the inhibition of the AXL-TGFβ-Hippo signaling axis. Citation Format: Josephine A. Taverna, Chia-Nung Hung, Chun-Lin Lin, Pawel A. Osmulski, Maria E. Gaczynska, Chiou-Miin Wang, Nicholas D. Lucio, Meizhen Chen, Chih-Wei Chou, Alia Nazarullah, Shellye R. Lampkin, Lianquin Qiu, David J. Bearss, Steve Warner, Lars Mouritsen, Mark Wade, Daniel DeArmond, Ruben Mesa, Nameer Kirma, Tim H.-M. Huang. AXL Inhibitor TP-0903 attenuates TGFβ-Hippo signaling in lung adenocarcinoma cells [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B29.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1557-3125.HIPPO19-B29
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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