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Article: Tumorigenesis driven by the BRAF

Gadal, Sunyana / Boyer, Jacob A / Roy, Simon F / Outmezguine, Noah A / Sharma, Malvika / Li, Hongyan / Fan, Ning / Chan, Eric / Romin, Yevgeniy / Barlas, Afsar / Chang, Qing / Pancholi, Priya / Timaul, Neilawattie Merna / Overholtzer, Michael / Yaeger, Rona / Manova-Todorova, Katia / de Stanchina, Elisa / Bosenberg, Marcus / Rosen, Neal

bioRxiv : the preprint server for biology

2024

Abstract: ... ...

Abstract	BRAF
Language	English
Publishing date	2024-04-20
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.21.568071
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Article ; Online: Multiplex Spatial Protein Detection by Combining Immunofluorescence with Immunohistochemistry.

Kang, Wenfei / Santella, Anthony / Rosiek, Eric / Pulina, Maria / Chan, Eric / Fan, Ning / Tipping, Murray J / Barlas, Afsar / Romin, Yevgeniy / Manova-Todorova, Katia

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2593, Page(s) 233–244

Abstract: Technologies for staining and imaging multiple antigens in single tissue sections are developing rapidly due to their potential to uncover spatial relationships between proteins with cellular resolution. Detections are performed simultaneously or ... ...

Abstract	Technologies for staining and imaging multiple antigens in single tissue sections are developing rapidly due to their potential to uncover spatial relationships between proteins with cellular resolution. Detections are performed simultaneously or sequentially depending on the approach. However, several technologies can detect limited numbers of antigens or require expensive equipment and reagents. Another serious concern is the lack of flexibility. Most commercialized reagents are validated for defined antibody panels, and introducing any changes is laborious and costly. In this chapter, we describe a method where we combine, for the first time, multiplexed IF followed by sequential immunohistochemistry (IHC) with AEC chromogen on Leica Bond staining processors with paraffin tissue sections. We present data for successful detection of 10 antigens in a single tissue section with preserved tissue integrity. Our method is designed for use with any combination of antibodies of interest, with images collected using whole slide scanners. We include an image viewing and image analysis workflow using nonlinear warping to combine all staining passes in a single full-resolution image of the entire tissue section, aligned at the single cell level.
MeSH term(s)	Immunohistochemistry ; Biomarkers, Tumor/metabolism ; Fluorescent Antibody Technique ; Staining and Labeling ; Proteins ; Antigens/analysis
Chemical Substances	Biomarkers, Tumor ; Proteins ; Antigens
Language	English
Publishing date	2022-12-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2811-9_15
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Article ; Online: Anti gC1qR/p32/HABP1 Antibody Therapy Decreases Tumor Growth in an Orthotopic Murine Xenotransplant Model of Triple Negative Breast Cancer.

Peerschke, Ellinor I / Stanchina, Elisa de / Chang, Qing / Manova-Todorova, Katia / Barlas, Afsar / Savitt, Anne G / Geisbrecht, Brian V / Ghebrehiwet, Berhane

Antibodies (Basel, Switzerland)

2020 Volume 9, Issue 4

Abstract: gC1qR is highly expressed in breast cancer and plays a role in cancer cell proliferation. This study explored therapy with gC1qR monoclonal antibody 60.11, directed against the C1q binding domain of gC1qR, in a murine orthotopic xenotransplant model of ... ...

Abstract	gC1qR is highly expressed in breast cancer and plays a role in cancer cell proliferation. This study explored therapy with gC1qR monoclonal antibody 60.11, directed against the C1q binding domain of gC1qR, in a murine orthotopic xenotransplant model of triple negative breast cancer. MDA231 breast cancer cells were injected into the mammary fat pad of athymic nu/nu female mice. Mice were segregated into three groups (
Language	English
Publishing date	2020-10-06
Publishing country	Switzerland
Document type	Journal Article
ISSN	2073-4468
ISSN (online)	2073-4468
DOI	10.3390/antib9040051
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Article: Single Cell Analysis of Treatment-Resistant Prostate Cancer: Implications of Cell State Changes for Cell Surface Antigen Targeted Therapies.

Zaidi, Samir / Park, Jooyoung / Chan, Joseph M / Roudier, Martine P / Zhao, Jimmy L / Gopalan, Anuradha / Wadosky, Kristine M / Patel, Radhika A / Sayar, Erolcan / Karthaus, Wouter R / Henry Kates, D / Chaudhary, Ojasvi / Xu, Tianhao / Masilionis, Ignas / Mazutis, Linas / Chaligné, Ronan / Obradovic, Aleksandar / Linkov, Irina / Barlas, Afsar /

Jungbluth, Achim / Rekhtman, Natasha / Silber, Joachim / Manova-Todorova, Katia / Watson, Philip A / True, Lawrence D / Morrissey, Colm M / Scher, Howard I / Rathkopf, Dana / Morris, Michael J / Goodrich, David W / Choi, Jungmin / Nelson, Peter S / Haffner, Michael C / Sawyers, Charles L

bioRxiv : the preprint server for biology

2024

Abstract: Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in ... ...

Abstract	Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)--a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis (TMA) on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated, but also found that the expression of molecules targeted therapeutically, namely
Language	English
Publishing date	2024-04-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.09.588340
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Article ; Online: Fluorescent Tissue Assessment of Colorectal Cancer Liver Metastases Ablation Zone: A Potential Real-Time Biomarker of Complete Tumor Ablation.

Sotirchos, Vlasios S / Fujisawa, Sho / Vakiani, Efsevia / Solomon, Stephen B / Manova-Todorova, Katia O / Sofocleous, Constantinos T

Annals of surgical oncology

2019 Volume 26, Issue 6, Page(s) 1833–1840

Abstract: Background: This study aimed to evaluate whether rapid fluorescent tissue examination immediately after colorectal cancer liver metastasis (CLM) ablation correlates with standard pathologic and immunohistochemical (IHC) assessments.: Methods: This ... ...

Abstract	Background: This study aimed to evaluate whether rapid fluorescent tissue examination immediately after colorectal cancer liver metastasis (CLM) ablation correlates with standard pathologic and immunohistochemical (IHC) assessments. Methods: This prospective, National Institutes of Health-supported study enrolled 34 consecutive patients with 53 CLMs ablated between January 2011 and December 2014. Immediately after ablation, core needle sampling of the ablation zone was performed. Tissue samples were evaluated with fluorescent viability (MitoTracker Red) and nuclear (Hoechst) stains. Confocal microscope imaging was performed within 30 min after ablation. The same samples were subsequently fixed and stained with hematoxylin and eosin (H&E). Identified tumor cells underwent IHC staining for proliferation (Ki67) and viability (OxPhos). The study pathologist, blinded to the H&E and IHC assessment, evaluated the fluorescent images separately to detect viable tumor cells. Sensitivity, specificity, and overall concordance of the fluorescent versus H&E and IHC assessments were calculated. Results: A total of 63 tissue samples were collected and processed. The overall concordance rate between the immediate fluorescent and the subsequent H&E and IHC assessments was 94% (59/63). The fluorescent assessment sensitivity and specificity for the identification of tumor cells were respectively 100% (18/18) and 91% (41/45). Conclusions: The study showed a high concordance rate between the immediate fluorescent assessment and the standard H&E and IHC assessment of the ablation zone. Given the documented prognostic value of ablation zone tissue characteristics for outcomes after ablation of CLM, the fluorescent assessment offers a potential intra-procedural biomarker of complete tumor ablation.
MeSH term(s)	Biomarkers, Tumor/analysis ; Catheter Ablation/methods ; Colorectal Neoplasms/diagnostic imaging ; Colorectal Neoplasms/pathology ; Colorectal Neoplasms/surgery ; Fluorescence ; Follow-Up Studies ; Humans ; Liver Neoplasms/diagnostic imaging ; Liver Neoplasms/secondary ; Liver Neoplasms/surgery ; Prognosis ; Prospective Studies ; Staining and Labeling/methods ; Tomography, X-Ray Computed/methods
Chemical Substances	Biomarkers, Tumor
Keywords	covid19
Language	English
Publishing date	2019-03-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	1200469-8
ISSN	1534-4681 ; 1068-9265
ISSN (online)	1534-4681
ISSN	1068-9265
DOI	10.1245/s10434-018-07133-6
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Article ; Online: Membrane-derived particles shed by PSMA-positive cells function as pro-angiogenic stimuli in tumors.

Journal of controlled release : official journal of the Controlled Release Society

2023 Volume 364, Page(s) 312–325

Abstract: Cell membrane-derived particles (Mp) are rounded membrane-enclosed particles that are shed from tumor cells. Mp are formed from tumor membranes and are capable of tumor targeting and immunotherapeutic agents because they share membrane homology with ... ...

Abstract	Cell membrane-derived particles (Mp) are rounded membrane-enclosed particles that are shed from tumor cells. Mp are formed from tumor membranes and are capable of tumor targeting and immunotherapeutic agents because they share membrane homology with parental cells; thus, they are under consideration as a drug delivery vehicle. Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein with enzymatic functionality, is highly expressed in Mp and extracellular vesicles (EV) from prostate cancer (PCa) with poor clinical prognosis. Although PSMA expression was previously shown in EV and Mp isolated from cell lines and from the blood of patients with high-grade PCa, no pathophysiological effects have been linked to PCa-derived Mp. Here, we compared Mp from PSMA-expressing (PSMA-Mp) and PSMA-non-expressing (WT-Mp) cells side by side in vitro and in vivo. PSMA-Mp can transfer PSMA and new phenotypic characteristics to the tumor microenvironment. The consequence of PSMA transfer to cells and increased secretion of vascular endothelial growth factor-A (VEGF-A), pro-angiogenic and pro-lymphangiogenic mediators, with increased 4E binding protein 1 (4EBP-1) phosphorylation.
MeSH term(s)	Male ; Humans ; Vascular Endothelial Growth Factor A ; Prostatic Neoplasms/pathology ; Cell Membrane/metabolism ; Tumor Microenvironment
Chemical Substances	Vascular Endothelial Growth Factor A
Language	English
Publishing date	2023-11-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2023.10.038
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Article: Allosteric interactions prime androgen receptor dimerization and activation

Molecular cell. 2022 June 02, v. 82, no. 11

2022

Abstract: The androgen receptor (AR) is a nuclear receptor that governs gene expression programs required for prostate development and male phenotype maintenance. Advanced prostate cancers display AR hyperactivation and transcriptome expansion, in part, through AR ...

Abstract	The androgen receptor (AR) is a nuclear receptor that governs gene expression programs required for prostate development and male phenotype maintenance. Advanced prostate cancers display AR hyperactivation and transcriptome expansion, in part, through AR amplification and interaction with oncoprotein cofactors. Despite its biological importance, how AR domains and cofactors cooperate to bind DNA has remained elusive. Using single-particle cryo-electron microscopy, we isolated three conformations of AR bound to DNA, showing that AR forms a non-obligate dimer, with the buried dimer interface utilized by ancestral steroid receptors repurposed to facilitate cooperative DNA binding. We identify novel allosteric surfaces which are compromised in androgen insensitivity syndrome and reinforced by AR’s oncoprotein cofactor, ERG, and by DNA-binding motifs. Finally, we present evidence that this plastic dimer interface may have been adopted for transactivation at the expense of DNA binding. Our work highlights how fine-tuning AR’s cooperative interactions translate to consequences in development and disease.
Keywords	DNA ; androgen receptors ; androgens ; cryo-electron microscopy ; dimerization ; gene expression ; males ; oncogene proteins ; phenotype ; transcriptional activation ; transcriptome
Language	English
Dates of publication	2022-0602
Size	p. 2021-2031.e5.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2022.03.035
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Article ; Online: Spatial mapping of the collagen distribution in human and mouse tissues by force volume atomic force microscopy.

Calò, Annalisa / Romin, Yevgeniy / Srouji, Rami / Zambirinis, Constantinos P / Fan, Ning / Santella, Anthony / Feng, Elvin / Fujisawa, Sho / Turkekul, Mesruh / Huang, Sharon / Simpson, Amber L / D'Angelica, Michael / Jarnagin, William R / Manova-Todorova, Katia

Scientific reports

2020 Volume 10, Issue 1, Page(s) 15664

Abstract: Changes in the elastic properties of living tissues during normal development and in pathological processes are often due to modifications of the collagen component of the extracellular matrix at various length scales. Force volume AFM can precisely ... ...

Abstract	Changes in the elastic properties of living tissues during normal development and in pathological processes are often due to modifications of the collagen component of the extracellular matrix at various length scales. Force volume AFM can precisely capture the mechanical properties of biological samples with force sensitivity and spatial resolution. The integration of AFM data with data of the molecular composition contributes to understanding the interplay between tissue biochemistry, organization and function. The detection of micrometer-size, heterogeneous domains at different elastic moduli in tissue sections by AFM has remained elusive so far, due to the lack of correlations with histological, optical and biochemical assessments. In this work, force volume AFM is used to identify collagen-enriched domains, naturally present in human and mouse tissues, by their elastic modulus. Collagen identification is obtained in a robust way and affordable timescales, through an optimal design of the sample preparation method and AFM parameters for faster scan with micrometer resolution. The choice of a separate reference sample stained for collagen allows correlating elastic modulus with collagen amount and position with high statistical significance. The proposed preparation method ensures safe handling of the tissue sections guarantees the preservation of their micromechanical characteristics over time and makes it much easier to perform correlation experiments with different biomarkers independently.
MeSH term(s)	Analytic Sample Preparation Methods ; Animals ; Biomechanical Phenomena ; Collagen/metabolism ; Cryopreservation ; Humans ; Mice ; Microscopy, Atomic Force ; Organ Specificity ; Protein Transport ; Tissue Fixation
Chemical Substances	Collagen (9007-34-5)
Language	English
Publishing date	2020-09-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-72564-9
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Article: gC1qR/HABP1/p32 Is a Potential New Therapeutic Target Against Mesothelioma.

Peerschke, Ellinor / Stier, Kenneth / Li, Xiaoyu / Kandov, Evelyn / de Stanchina, Elisa / Chang, Qing / Xiong, Yuquan / Manova-Todorova, Katia / Fan, Ning / Barlas, Afsar / Ghebrehiwet, Berhane / Adusumilli, Prasad S

Frontiers in oncology

2020 Volume 10, Page(s) 1413

Abstract: Mesothelioma is an aggressive cancer of the serous membranes with poor prognosis despite combination therapy consisting of surgery, radiotherapy, and platinum-based chemotherapy. Targeted therapies, including immunotherapies, have reported limited ... ...

Abstract	Mesothelioma is an aggressive cancer of the serous membranes with poor prognosis despite combination therapy consisting of surgery, radiotherapy, and platinum-based chemotherapy. Targeted therapies, including immunotherapies, have reported limited success, suggesting the need for additional therapeutic targets. This study investigates a potential new therapeutic target, gC1qR/HABP1/p32 (gC1qR), which is overexpressed in all morphologic subtypes of mesothelioma. gC1qR is a complement receptor that is associated with several cellular functions, including cell proliferation and angiogenesis.
Language	English
Publishing date	2020-08-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2020.01413
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Article ; Online: Tumor-targeted nanoparticles improve the therapeutic index of BCL2 and MCL1 dual inhibition.

Bala Tannan, Neeta / Manzari, Mandana T / Herviou, Laurie / Da Silva Ferreira, Mariana / Hagen, Connor / Kiguchi, Hiroto / Manova-Todorova, Katia / Seshan, Venkatraman / de Stanchina, Elisa / Heller, Daniel A / Younes, Anas

Blood

2020 Volume 137, Issue 15, Page(s) 2057–2069

Abstract: Cancer and normal cells use multiple antiapoptotic BCL2 proteins to prevent cell death. Therapeutic targeting of multiple BCL2 family proteins enhances tumor killing but is also associated with increased systemic toxicity. Here, we demonstrate that the ... ...

Abstract	Cancer and normal cells use multiple antiapoptotic BCL2 proteins to prevent cell death. Therapeutic targeting of multiple BCL2 family proteins enhances tumor killing but is also associated with increased systemic toxicity. Here, we demonstrate that the dual targeting of MCL1 and BCL2 proteins using the small molecules S63845 and venetoclax induces durable remissions in mice that harbor human diffuse large B-cell lymphoma (DLBCL) tumors but is accompanied by hematologic toxicity and weight loss. To mitigate these toxicities, we encapsulated S63845 or venetoclax into nanoparticles that target P-selectin, which is enriched in tumor endothelial cells. In vivo and ex vivo imaging demonstrated preferential targeting of the nanoparticles to lymphoma tumors over vital organs. Mass spectrometry analyses after administration of nanoparticle drugs confirmed tumor enrichment of the drug while reducing plasma levels. Furthermore, nanoparticle encapsulation allowed 3.5- to 6.5-fold reduction in drug dose, induced sustained remissions, and minimized toxicity. Our results support the development of nanoparticles to deliver BH3 mimetic combinations in lymphoma and in general for toxic drugs in cancer therapy.
MeSH term(s)	Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/therapeutic use ; Bridged Bicyclo Compounds, Heterocyclic/administration & dosage ; Bridged Bicyclo Compounds, Heterocyclic/adverse effects ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use ; Cell Line, Tumor ; Drug Carriers/chemistry ; Drug Delivery Systems ; Female ; Humans ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Lymphoma, Large B-Cell, Diffuse/metabolism ; Mice ; Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Nanoparticles/chemistry ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Pyrimidines/administration & dosage ; Pyrimidines/adverse effects ; Pyrimidines/therapeutic use ; Sulfonamides/administration & dosage ; Sulfonamides/adverse effects ; Sulfonamides/therapeutic use ; Therapeutic Index ; Thiophenes/administration & dosage ; Thiophenes/adverse effects ; Thiophenes/therapeutic use
Chemical Substances	Antineoplastic Agents ; BCL2 protein, human ; Bridged Bicyclo Compounds, Heterocyclic ; Drug Carriers ; MCL1 protein, human ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2 ; Pyrimidines ; S63845 ; Sulfonamides ; Thiophenes ; venetoclax (N54AIC43PW)
Language	English
Publishing date	2020-10-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2020008017
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