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Article ; Online: Semaphorins as Regulators of Phenotypic Plasticity and Functional Reprogramming of Cancer Cells.

Gurrapu, Sreeharsha / Tamagnone, Luca

2019 Volume 25, Issue 4, Page(s) 303–314

Abstract: Semaphorins, initially found as neuronal guidance cues in embryo development, are now appreciated as major regulators of tissue morphogenesis and homeostasis, as well as of cancer progression. In fact, semaphorin signals have a profound impact on cell ... ...

Abstract	Semaphorins, initially found as neuronal guidance cues in embryo development, are now appreciated as major regulators of tissue morphogenesis and homeostasis, as well as of cancer progression. In fact, semaphorin signals have a profound impact on cell morphology, which has been commonly associated with the ability to regulate monomeric GTPases, cell-substrate adhesion, and cytoskeletal dynamics. Recently, however, several reports have indicated a novel and additional function of diverse semaphorins in the regulation of gene expression and cell phenotype plasticity. In this review article, we discuss these novel findings, focusing on the role of semaphorin signals in the regulation of bi-directional epithelial-mesenchymal transitions, stem cell properties, and drug resistance, which greatly contribute to the pathogenesis of cancer.
MeSH term(s)	Adaptation, Physiological ; Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cellular Reprogramming/genetics ; Drug Resistance, Neoplasm/genetics ; Epithelial-Mesenchymal Transition/genetics ; Humans ; Neoplasms/drug therapy ; Neoplasms/etiology ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Semaphorins/genetics ; Semaphorins/metabolism ; Signal Transduction
Chemical Substances	Antineoplastic Agents ; Semaphorins
Language	English
Publishing date	2019-02-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2036490-8
ISSN	1471-499X ; 1471-4914
ISSN (online)	1471-499X
ISSN	1471-4914
DOI	10.1016/j.molmed.2019.01.010
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Article ; Online: LncRNA Malat1 suppresses pyroptosis and T cell-mediated killing of incipient metastatic cells.

Kumar, Dhiraj / Gurrapu, Sreeharsha / Wang, Yan / Bae, Seong-Yeon / Pandey, Poonam R / Chen, Hong / Mondal, Jayanta / Han, Hyunho / Wu, Chang-Jiun / Karaiskos, Spyros / Yang, Fei / Sahin, Aysegul / Wistuba, Ignacio I / Gao, Jianjun / Tripathy, Debasish / Gao, Hua / Izar, Benjamin / Giancotti, Filippo G

Nature cancer

2024 Volume 5, Issue 2, Page(s) 262–282

Abstract: The contribution of antitumor immunity to metastatic dormancy is poorly understood. Here we show that the long noncoding RNA Malat1 is required for tumor initiation and metastatic reactivation in mouse models of breast cancer and other tumor types. ... ...

Abstract	The contribution of antitumor immunity to metastatic dormancy is poorly understood. Here we show that the long noncoding RNA Malat1 is required for tumor initiation and metastatic reactivation in mouse models of breast cancer and other tumor types. Malat1 localizes to nuclear speckles to couple transcription, splicing and mRNA maturation. In metastatic cells, Malat1 induces WNT ligands, autocrine loops to promote self-renewal and the expression of Serpin protease inhibitors. Through inhibition of caspase-1 and cathepsin G, SERPINB6B prevents gasdermin D-mediated induction of pyroptosis. In this way, SERPINB6B suppresses immunogenic cell death and confers evasion of T cell-mediated tumor lysis of incipient metastatic cells. On-target inhibition of Malat1 using therapeutic antisense nucleotides suppresses metastasis in a SERPINB6B-dependent manner. These results suggest that Malat1-induced expression of SERPINB6B can titrate pyroptosis and immune recognition at metastatic sites. Thus, Malat1 is at the nexus of tumor initiation, reactivation and immune evasion and represents a tractable and clinically relevant drug target.
MeSH term(s)	Animals ; Mice ; Cell Line, Tumor ; Pyroptosis ; RNA Splicing ; RNA, Long Noncoding/genetics ; T-Lymphocytes/metabolism
Chemical Substances	RNA, Long Noncoding ; Malat1 long non-coding RNA, mouse
Language	English
Publishing date	2024-01-09
Publishing country	England
Document type	Journal Article
ISSN	2662-1347
ISSN (online)	2662-1347
DOI	10.1038/s43018-023-00695-9
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Article ; Online: Transmembrane semaphorins: Multimodal signaling cues in development and cancer.

Gurrapu, Sreeharsha / Tamagnone, Luca

Cell adhesion & migration

2016 Volume 10, Issue 6, Page(s) 675–691

Abstract: Semaphorins constitute a large family of membrane-bound and secreted proteins that provide guidance cues for axon pathfinding and cell migration. Although initially discovered as repelling cues for axons in nervous system, they have been found to ... ...

Abstract	Semaphorins constitute a large family of membrane-bound and secreted proteins that provide guidance cues for axon pathfinding and cell migration. Although initially discovered as repelling cues for axons in nervous system, they have been found to regulate cell adhesion and motility, angiogenesis, immune function and tumor progression. Notably, semaphorins are bifunctional cues and for instance can mediate both repulsive and attractive functions in different contexts. While many studies focused so far on the function of secreted family members, class 1 semaphorins in invertebrates and class 4, 5 and 6 in vertebrate species comprise around 14 transmembrane semaphorin molecules with emerging functional relevance. These can signal in juxtacrine, paracrine and autocrine fashion, hence mediating long and short range repulsive and attractive guidance cues which have a profound impact on cellular morphology and functions. Importantly, transmembrane semaphorins are capable of bidirectional signaling, acting both in "forward" mode via plexins (sometimes in association with receptor tyrosine kinases), and in "reverse" manner through their cytoplasmic domains. In this review, we will survey known molecular mechanisms underlying the functions of transmembrane semaphorins in development and cancer.
MeSH term(s)	Animals ; Cell Membrane/metabolism ; Embryonic Development ; Humans ; Neoplasms/metabolism ; Receptors, Cell Surface/metabolism ; Semaphorins/metabolism ; Signal Transduction
Chemical Substances	Receptors, Cell Surface ; Semaphorins
Language	English
Publishing date	2016-06-13
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ISSN	1933-6926
ISSN (online)	1933-6926
DOI	10.1080/19336918.2016.1197479
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Sema4C/PlexinB2 signaling controls breast cancer cell growth, hormonal dependence and tumorigenic potential.

Gurrapu, Sreeharsha / Pupo, Emanuela / Franzolin, Giulia / Lanzetti, Letizia / Tamagnone, Luca

Cell death and differentiation

2018 Volume 25, Issue 7, Page(s) 1259–1275

Abstract: Semaphorin 4C (Sema4C) expression in human breast cancers correlates with poor disease outcome. Surprisingly, upon knock-down of Sema4C or its receptor PlexinB2 in diverse mammary carcinoma cells (but not their normal counterparts), we observed dramatic ... ...

Abstract	Semaphorin 4C (Sema4C) expression in human breast cancers correlates with poor disease outcome. Surprisingly, upon knock-down of Sema4C or its receptor PlexinB2 in diverse mammary carcinoma cells (but not their normal counterparts), we observed dramatic growth inhibition associated with impairment of G2/M phase transition, cytokinesis defects and the onset of cell senescence. Mechanistically, we demonstrated a Sema4C/PlexinB2/LARG-dependent signaling cascade that is required to maintain critical RhoA-GTP levels in cancer cells. Interestingly, we also found that Sema4C upregulation in luminal-type breast cancer cells drives a dramatic phenotypic change, with disassembly of polarity complexes, mitotic spindle misorientation, cell-cell dissociation and increased migration and invasiveness. We found that this signaling cascade is dependent on the PlexinB2 effectors ErbB2 and RhoA-dependent kinases. Moreover, Sema4C-overexpressing luminal breast cancer cells upregulated the transcription factors Snail, Slug and SOX-2, and formed estrogen-independent metastatic tumors in mice. In sum, our data indicate that Sema4C/PlexinB2 signaling is essential for the growth of breast carcinoma cells, featuring a novel potential therapeutic target. In addition, elevated Sema4C expression enables indolent luminal-type tumors to become resistant to estrogen deprivation, invasive and metastatic in vivo, which could account for its association with a subset of human breast cancers with poor prognosis.
MeSH term(s)	Animals ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Estrogens/metabolism ; Estrogens/pharmacology ; Female ; Humans ; MCF-7 Cells ; Mice ; Mice, Nude ; Mice, SCID ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Receptor, ErbB-2/genetics ; Receptor, ErbB-2/metabolism ; Semaphorins/genetics ; Semaphorins/metabolism ; Signal Transduction/drug effects ; Signal Transduction/genetics
Chemical Substances	Estrogens ; Nerve Tissue Proteins ; PLXNB2 protein, human ; Sema4c protein, human ; Semaphorins ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1)
Language	English
Publishing date	2018-03-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225672-9
ISSN	1476-5403 ; 1350-9047
ISSN (online)	1476-5403
ISSN	1350-9047
DOI	10.1038/s41418-018-0097-4
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Article ; Online: PlexinD1 Is a Novel Transcriptional Target and Effector of Notch Signaling in Cancer Cells.

Rehman, Michael / Gurrapu, Sreeharsha / Cagnoni, Gabriella / Capparuccia, Lorena / Tamagnone, Luca

PloS one

2016 Volume 11, Issue 10, Page(s) e0164660

Abstract: The secreted semaphorin Sema3E controls cell migration and invasiveness in cancer cells. Sema3E-receptor, PlexinD1, is frequently upregulated in melanoma, breast, colon, ovarian and prostate cancers; however, the mechanisms underlying PlexinD1 ... ...

Abstract	The secreted semaphorin Sema3E controls cell migration and invasiveness in cancer cells. Sema3E-receptor, PlexinD1, is frequently upregulated in melanoma, breast, colon, ovarian and prostate cancers; however, the mechanisms underlying PlexinD1 upregulation and the downstream events elicited in tumor cells are still unclear. Here we show that the canonical RBPjk-dependent Notch signaling cascade controls PlexinD1 expression in primary endothelial and cancer cells. Transcriptional activation was studied by quantitative PCR and promoter activity reporter assays. We found that Notch ligands and constitutively activated intracellular forms of Notch receptors upregulated PlexinD1 expression; conversely RNAi-based knock-down, or pharmacological inhibition of Notch signaling by gamma-secretase inhibitors, downregulated PlexinD1 levels. Notably, both Notch1 and Notch3 expression positively correlates with PlexinD1 levels in prostate cancer, as well as in other tumor types. In prostate cancer cells, Sema3E-PlexinD1 axis was previously reported to regulate migration; however, implicated mechanisms were not elucidated. Here we show that in these cells PlexinD1 activity induces the expression of the transcription factor Slug, downregulates E-cadherin levels and enhances cell migration. Moreover, our mechanistic data identify PlexinD1 as a pivotal mediator of this signaling axis downstream of Notch in prostate cancer cells. In fact, on one hand, PlexinD1 is required to mediate cell migration and E-cadherin regulation elicited by Notch. On the other hand, PlexinD1 upregulation is sufficient to induce prostate cancer cell migration and metastatic potential in mice, leading to functional rescue in the absence of Notch. In sum, our work identifies PlexinD1 as a novel transcriptional target induced by Notch signaling, and reveals its role promoting prostate cancer cell migration and downregulating E-cadherin levels in Slug-dependent manner. Collectively, these findings suggest that Notch-PlexinD1 signaling axis may be targeted to impair prostate cancer cell invasiveness and metastasis.
MeSH term(s)	Animals ; Benzazepines/pharmacology ; Cadherins/genetics ; Cadherins/metabolism ; Cell Adhesion Molecules, Neuronal/antagonists & inhibitors ; Cell Adhesion Molecules, Neuronal/genetics ; Cell Adhesion Molecules, Neuronal/metabolism ; Cell Line, Tumor ; Cell Movement/drug effects ; Diamines/pharmacology ; Down-Regulation/drug effects ; Enzyme Inhibitors/pharmacology ; HEK293 Cells ; Human Umbilical Vein Endothelial Cells ; Humans ; Intracellular Signaling Peptides and Proteins ; Jagged-1 Protein/pharmacology ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Membrane Glycoproteins ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Microscopy, Fluorescence ; Promoter Regions, Genetic ; RNA Interference ; RNA, Messenger/metabolism ; RNA, Small Interfering/metabolism ; Receptors, Notch/antagonists & inhibitors ; Receptors, Notch/genetics ; Receptors, Notch/metabolism ; Signal Transduction/drug effects ; Snail Family Transcription Factors/genetics ; Snail Family Transcription Factors/metabolism ; Thiazoles/pharmacology ; Transplantation, Heterologous ; Up-Regulation/drug effects
Chemical Substances	24-diamino-5-phenylthiazole ; Benzazepines ; Cadherins ; Cell Adhesion Molecules, Neuronal ; Diamines ; Enzyme Inhibitors ; Intracellular Signaling Peptides and Proteins ; JAG1 protein, human ; Jagged-1 Protein ; Membrane Glycoproteins ; PLXND1 protein, human ; RNA, Messenger ; RNA, Small Interfering ; Receptors, Notch ; SNAI1 protein, human ; Snail Family Transcription Factors ; Thiazoles ; 2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide (KK8645V7LE)
Language	English
Publishing date	2016-10-17
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0164660
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: SARS-CoV-2 Exploits Sexually Dimorphic and Adaptive IFN and TNFa Signaling to Gain Entry into Alveolar Epithelium

Giancotti, Filippo / Wang, Yan / Gurrapu, Sreeharsha / Chen, Hong / Laudato, Sara / Caggiano, Emily / Jiang, Yan / Ling, Hsiang-Hsi

bioRxiv

Abstract: Infection of the alveolar epithelium constitutes a bottleneck in the progression of COVID-19 to SARS presumably due to the paucity of viral entry receptors in alveolar epithelial type 1 and 2 cells. We have found that the male alveolar epithelial cells ... ...

Abstract	Infection of the alveolar epithelium constitutes a bottleneck in the progression of COVID-19 to SARS presumably due to the paucity of viral entry receptors in alveolar epithelial type 1 and 2 cells. We have found that the male alveolar epithelial cells express twice as many ACE2 and TMPRSS2 entry receptors as the female ones. Intriguingly, IFN and TNF-α signaling are preferentially active in male alveolar cells and induce binding of the cognate transcription factors to the promoters and lung-active enhancers of ACE2 and TMPRSS2. Cotreatment with IFN-I and III dramatically increases expression of the receptors and viral entry in alveolar epithelial cells. TNFα and IFN-II, typically overproduced during the cytokine storm, similarly collaborate to induce these events. Whereas JAK inhibitors suppress viral entry induced by IFN-I/III, simultaneous inhibition of IKK/NF-κB is necessary to block viral entry induced by TNFα and IFN II. In addition to explaining the increased incidence of SARS in males, these findings indicate that SARS-Cov-2 hijacks epithelial immune signaling to promote infection of the alveolar epithelium and suggest that JAK inhibitors, singly and in combination with NF-KB inhibitors, may exhibit efficacy in preventing or treating COVID-19 SARS.
Keywords	covid19
Language	English
Publishing date	2021-07-23
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.07.23.453505
Database	COVID19

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Article ; Online: Reverse signaling by semaphorin 4C elicits SMAD1/5- and ID1/3-dependent invasive reprogramming in cancer cells.

Gurrapu, Sreeharsha / Franzolin, Giulia / Fard, Damon / Accardo, Massimo / Medico, Enzo / Sarotto, Ivana / Sapino, Anna / Isella, Claudio / Tamagnone, Luca

Science signaling

2019 Volume 12, Issue 595

Abstract: Semaphorins are a family of molecular signals that guide cell migration and are implicated in the regulation of cancer cells. In particular, transmembrane semaphorins are postulated to act as both ligands ("forward" mode) and signaling receptors (" ... ...

Abstract	Semaphorins are a family of molecular signals that guide cell migration and are implicated in the regulation of cancer cells. In particular, transmembrane semaphorins are postulated to act as both ligands ("forward" mode) and signaling receptors ("reverse" mode); however, reverse semaphorin signaling in cancer is relatively less understood. Here, we identified a previously unknown function of transmembrane semaphorin 4C (Sema4C), acting in reverse mode, to elicit nonconventional TGF-β/BMP receptor activation and selective SMAD1/5 phosphorylation. Sema4C coimmunoprecipitated with TGFBRII and BMPR1, supporting its role as modifier of this pathway. Sema4C reverse signaling led to the increased abundance of ID1/3 transcriptional factors and to extensive reprogramming of gene expression, which suppressed the typical features of the epithelial-mesenchymal transition in invasive carcinoma cells. This phenotype was nevertheless coupled with burgeoning metastatic behavior in vivo, consistent with evidence that Sema4C expression correlates with metastatic progression in human breast cancers. Thus, Sema4C reverse signaling promoted SMAD1/5- and ID1/3-dependent gene expression reprogramming and phenotypic plasticity in invasive cancer cells.
MeSH term(s)	Animals ; COS Cells ; Chlorocebus aethiops ; Humans ; Inhibitor of Differentiation Protein 1/genetics ; Inhibitor of Differentiation Protein 1/metabolism ; Inhibitor of Differentiation Proteins/genetics ; Inhibitor of Differentiation Proteins/metabolism ; Neoplasm Invasiveness ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; PC-3 Cells ; Semaphorins/genetics ; Semaphorins/metabolism ; Signal Transduction ; Smad1 Protein/genetics ; Smad1 Protein/metabolism ; Smad3 Protein/genetics ; Smad3 Protein/metabolism
Chemical Substances	ID1 protein, human ; Inhibitor of Differentiation Protein 1 ; Inhibitor of Differentiation Proteins ; Neoplasm Proteins ; SMAD1 protein, human ; SMAD3 protein, human ; Sema4c protein, human ; Semaphorins ; Smad1 Protein ; Smad3 Protein ; ID3 protein, human (147785-34-0)
Language	English
Publishing date	2019-08-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.aav2041
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Article ; Online: PlexinD1 Is a Novel Transcriptional Target and Effector of Notch Signaling in Cancer Cells.

Michael Rehman / Sreeharsha Gurrapu / Gabriella Cagnoni / Lorena Capparuccia / Luca Tamagnone

PLoS ONE, Vol 11, Iss 10, p e

2016 Volume 0164660

Abstract	The secreted semaphorin Sema3E controls cell migration and invasiveness in cancer cells. Sema3E-receptor, PlexinD1, is frequently upregulated in melanoma, breast, colon, ovarian and prostate cancers; however, the mechanisms underlying PlexinD1 upregulation and the downstream events elicited in tumor cells are still unclear. Here we show that the canonical RBPjk-dependent Notch signaling cascade controls PlexinD1 expression in primary endothelial and cancer cells. Transcriptional activation was studied by quantitative PCR and promoter activity reporter assays. We found that Notch ligands and constitutively activated intracellular forms of Notch receptors upregulated PlexinD1 expression; conversely RNAi-based knock-down, or pharmacological inhibition of Notch signaling by gamma-secretase inhibitors, downregulated PlexinD1 levels. Notably, both Notch1 and Notch3 expression positively correlates with PlexinD1 levels in prostate cancer, as well as in other tumor types. In prostate cancer cells, Sema3E-PlexinD1 axis was previously reported to regulate migration; however, implicated mechanisms were not elucidated. Here we show that in these cells PlexinD1 activity induces the expression of the transcription factor Slug, downregulates E-cadherin levels and enhances cell migration. Moreover, our mechanistic data identify PlexinD1 as a pivotal mediator of this signaling axis downstream of Notch in prostate cancer cells. In fact, on one hand, PlexinD1 is required to mediate cell migration and E-cadherin regulation elicited by Notch. On the other hand, PlexinD1 upregulation is sufficient to induce prostate cancer cell migration and metastatic potential in mice, leading to functional rescue in the absence of Notch. In sum, our work identifies PlexinD1 as a novel transcriptional target induced by Notch signaling, and reveals its role promoting prostate cancer cell migration and downregulating E-cadherin levels in Slug-dependent manner. Collectively, these findings suggest that Notch-PlexinD1 signaling axis may be targeted to ...
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis.

Han, Hyunho / Wang, Yan / Curto, Josue / Gurrapu, Sreeharsha / Laudato, Sara / Rumandla, Alekya / Chakraborty, Goutam / Wang, Xiaobo / Chen, Hong / Jiang, Yan / Kumar, Dhiraj / Caggiano, Emily G / Capogiri, Monica / Zhang, Boyu / Ji, Yan / Maity, Sankar N / Hu, Min / Bai, Shanshan / Aparicio, Ana M /

Efstathiou, Eleni / Logothetis, Christopher J / Navin, Nicholas / Navone, Nora M / Chen, Yu / Giancotti, Filippo G

Cell reports

2022 Volume 39, Issue 1, Page(s) 110595

Abstract: Bioinformatic analysis of 94 patient-derived xenografts (PDXs), cell lines, and organoids (PCOs) identifies three intrinsic transcriptional subtypes of metastatic castration-resistant prostate cancer: androgen receptor (AR) pathway + prostate cancer (PC) ...

Abstract	Bioinformatic analysis of 94 patient-derived xenografts (PDXs), cell lines, and organoids (PCOs) identifies three intrinsic transcriptional subtypes of metastatic castration-resistant prostate cancer: androgen receptor (AR) pathway + prostate cancer (PC) (ARPC), mesenchymal and stem-like PC (MSPC), and neuroendocrine PC (NEPC). A sizable proportion of castration-resistant and metastatic stage PC (M-CRPC) cases are admixtures of ARPC and MSPC. Analysis of clinical datasets and mechanistic studies indicates that MSPC arises from ARPC as a consequence of therapy-induced lineage plasticity. AR blockade with enzalutamide induces (1) transcriptional silencing of TP53 and hence dedifferentiation to a hybrid epithelial and mesenchymal and stem-like state and (2) inhibition of BMP signaling, which promotes resistance to AR inhibition. Enzalutamide-tolerant LNCaP cells re-enter the cell cycle in response to neuregulin and generate metastasis in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibits efficacy in models of ARPC and MSPC or MSPC, respectively. These results define MSPC, trace its origin to therapy-induced lineage plasticity, and reveal its sensitivity to HER2/3 inhibition.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Benzamides ; Carcinoma, Neuroendocrine ; Cell Line, Tumor ; Cell Plasticity/drug effects ; Cell Plasticity/physiology ; Drug Resistance, Neoplasm ; Humans ; Male ; Mice ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Nitriles ; Phenylthiohydantoin ; Prostatic Neoplasms, Castration-Resistant/drug therapy ; Prostatic Neoplasms, Castration-Resistant/genetics ; Prostatic Neoplasms, Castration-Resistant/metabolism ; Receptors, Androgen/drug effects ; Receptors, Androgen/metabolism ; Signal Transduction ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/physiology
Chemical Substances	Antineoplastic Agents ; Benzamides ; Nitriles ; Receptors, Androgen ; Phenylthiohydantoin (2010-15-3) ; enzalutamide (93T0T9GKNU)
Language	English
Publishing date	2022-04-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.110595
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Article ; Online: Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis

Cell Reports, Vol 39, Iss 1, Pp 110595- (2022)

2022

Abstract: Summary: Bioinformatic analysis of 94 patient-derived xenografts (PDXs), cell lines, and organoids (PCOs) identifies three intrinsic transcriptional subtypes of metastatic castration-resistant prostate cancer: androgen receptor (AR) pathway + prostate ... ...

Abstract	Summary: Bioinformatic analysis of 94 patient-derived xenografts (PDXs), cell lines, and organoids (PCOs) identifies three intrinsic transcriptional subtypes of metastatic castration-resistant prostate cancer: androgen receptor (AR) pathway + prostate cancer (PC) (ARPC), mesenchymal and stem-like PC (MSPC), and neuroendocrine PC (NEPC). A sizable proportion of castration-resistant and metastatic stage PC (M-CRPC) cases are admixtures of ARPC and MSPC. Analysis of clinical datasets and mechanistic studies indicates that MSPC arises from ARPC as a consequence of therapy-induced lineage plasticity. AR blockade with enzalutamide induces (1) transcriptional silencing of TP53 and hence dedifferentiation to a hybrid epithelial and mesenchymal and stem-like state and (2) inhibition of BMP signaling, which promotes resistance to AR inhibition. Enzalutamide-tolerant LNCaP cells re-enter the cell cycle in response to neuregulin and generate metastasis in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibits efficacy in models of ARPC and MSPC or MSPC, respectively. These results define MSPC, trace its origin to therapy-induced lineage plasticity, and reveal its sensitivity to HER2/3 inhibition.
Keywords	CP: Cancer ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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