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Article: α-Mangostin Promotes In Vitro and In Vivo Degradation of Androgen Receptor and AR-V7 Splice Variant in Prostate Cancer Cells.

Nauman, Mirielle C / Won, Jong Hoon / Petiwala, Sakina M / Vemu, Bhaskar / Lee, Hyun / Sverdlov, Maria / Johnson, Jeremy J

Cancers

2023 Volume 15, Issue 7

Abstract: A major limitation of current prostate cancer pharmacotherapy approaches is the inability of these compounds to target androgen receptor variants or mutants that develop during prostate cancer progression. The demand for novel therapeutics to prevent, ... ...

Abstract	A major limitation of current prostate cancer pharmacotherapy approaches is the inability of these compounds to target androgen receptor variants or mutants that develop during prostate cancer progression. The demand for novel therapeutics to prevent, slow, and treat prostate cancer is significant because FDA approved anti-androgens are associated with adverse events and can eventually drive drug-resistant prostate cancer. This study evaluated α-mangostin for its novel ability to degrade the androgen receptor and androgen receptor variants. α-Mangostin is one of more than 70 isoprenylated xanthones isolated from
Language	English
Publishing date	2023-04-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15072118
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Article: Machine Learning for Digital Scoring of PRMT6 in Immunohistochemical Labeled Lung Cancer.

Mahmoud, Abeer M / Brister, Eileen / David, Odile / Valyi-Nagy, Klara / Sverdlov, Maria / Gann, Peter H / Kim, Sage J

Cancers

2023 Volume 15, Issue 18

Abstract: Lung cancer is the leading cause of cancer death in the U.S. Therefore, it is imperative to identify novel biomarkers for the early detection and progression of lung cancer. PRMT6 is associated with poor lung cancer prognosis. However, analyzing PRMT6 ... ...

Abstract	Lung cancer is the leading cause of cancer death in the U.S. Therefore, it is imperative to identify novel biomarkers for the early detection and progression of lung cancer. PRMT6 is associated with poor lung cancer prognosis. However, analyzing PRMT6 expression manually in large samples is time-consuming posing a significant limitation for processing this biomarker. To overcome this issue, we trained and validated an automated method for scoring PRMT6 in lung cancer tissues, which can then be used as the standard method in future larger cohorts to explore population-level associations between PRMT6 expression and sociodemographic/clinicopathologic characteristics. We evaluated the ability of a trained artificial intelligence (AI) algorithm to reproduce the PRMT6 immunoreactive scores obtained by pathologists. Our findings showed that tissue segmentation to cancer vs. non-cancer tissues was the most critical parameter, which required training and adjustment of the algorithm to prevent scoring non-cancer tissues or ignoring relevant cancer cells. The trained algorithm showed a high concordance with pathologists with a correlation coefficient of 0.88. The inter-rater agreement was significant, with an intraclass correlation of 0.95 and a scale reliability coefficient of 0.96. In conclusion, we successfully optimized a machine learning algorithm for scoring PRMT6 expression in lung cancer that matches the degree of accuracy of scoring by pathologists.
Language	English
Publishing date	2023-09-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15184582
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Article: Multiplex Imaging Reveals Novel Subcellular, Microenvironmental, and Racial Patterns of MRTFA/B Activation in Invasive Breast Cancers and Metastases.

Wilk, Stephanie M / Lee, Kihak / Gajda, Alexa M / Haloul, Mohamed / Macias, Virgilia / Wiley, Elizabeth L / Chen, Zhengjia / Liu, Xinyi / Wang, Xiaowei / Sverdlov, Maria / Hoskins, Kent F / Emrah, Ekrem

bioRxiv : the preprint server for biology

2024

Abstract: Breast cancer progression and metastasis involve the action of multiple transcription factors in tumors and in the cells of the tumor microenvironment (TME) and understanding how these transcription factors are coordinated can guide novel therapeutic ... ...

Abstract	Breast cancer progression and metastasis involve the action of multiple transcription factors in tumors and in the cells of the tumor microenvironment (TME) and understanding how these transcription factors are coordinated can guide novel therapeutic strategies. Myocardin related transcription factors A and B (MRTFA/B) are two related transcription factors that redundantly control cancer cell invasion and metastasis in mouse models of breast cancer, but their roles in human cancer are incompletely understood. Here, we used a combination of multiplexed immunofluorescence and bioinformatics analyses to show that MRTFA/B are concurrently activated in tumor cells, but they show distinct patterns of expression across different histological subtypes and in the TME. Importantly, MRTFA expression was elevated in metastatic tumors of African American patients, who disproportionately die from breast cancer. Interestingly, in contrast to publicly available mRNA expression data, MRTFA was similarly expressed across estrogen receptor (ER) positive and negative breast tumors, while MRTFB expression was highest in ER+ breast tumors. Furthermore, MRTFA was specifically expressed in the perivascular antigen presenting cells (APCs) and its expression correlated with the expression of the immune checkpoint protein V-set immunoregulatory receptor (VSIR). These results provide unique insights into how MRTFA and MRTFB can promote metastasis in human cancer, into the racial disparities of their expression patterns, and their function within the complex breast cancer TME.
Language	English
Publishing date	2024-01-08
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.03.573909
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Article ; Online: Regulation of SELENOF translation by eIF4a3: Possible role in prostate cancer progression.

Bera, Soumen / Kadkol, Shrinidhi / Hong, Lenny K / Ali, Waleed / Brockman, John D / Sverdlov, Maria / Brister, Eileen / Macais, Virgilia / Kajdacsy-Balla, Andre / Valyi-Nagy, Klara / Xu, Ziqiao / Kastrati, Irida / Liu, Li / Diamond, Alan M

Molecular carcinogenesis

2023 Volume 62, Issue 12, Page(s) 1803–1816

Abstract: The levels of the SELENOF selenoprotein are dramatically reduced in prostate cancer compared to adjacent benign tissue and reducing SELENOF in prostate epithelial cells results in the acquisition of features of the transformed phenotype. It was ... ...

Abstract	The levels of the SELENOF selenoprotein are dramatically reduced in prostate cancer compared to adjacent benign tissue and reducing SELENOF in prostate epithelial cells results in the acquisition of features of the transformed phenotype. It was hypothesized that the aberrant increase in the eiF4a3 translation factor, which has an established role in RNA splicing and the regulation of selenoprotein translation, contributes to the lower levels of SELENOF. Using the available databases, eIF4a3 messenger RNA (mRNA) levels are elevated in prostate cancer compared to normal tissue as is the hypomethylation of the corresponding gene. Using a prostate cancer tissue microarray, we established that eiF4a3 levels are higher in prostate cancer tissue. Ectopic expression of eIF4a3 in prostate cancer cells reduced SELENOF levels and attenuated the readthrough of the UGA codon using a specialized reporter construct designed to examine UGA decoding, with the opposite effects observed using eIF4a3 knock-down constructs. Direct binding of eIF4a3 to the regulatory regions of SELENOF mRNA was established with pull-down experiments. Lastly, we show that an eIF4a3 inhibitor, eIF4a3-IN-2, increases SELENOF levels, UGA readthrough, and reduces binding of eIF4a3 to the SELENOF mRNA 3'-UTR in exposed cells. These data establish eIF4a3 as a likely prostate cancer oncogene and a regulator of SELENOF translation.
MeSH term(s)	Male ; Humans ; Prostate/metabolism ; Selenoproteins/genetics ; Prostatic Neoplasms/genetics ; Codon, Terminator ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
Chemical Substances	Selenoproteins ; Codon, Terminator ; RNA, Messenger
Language	English
Publishing date	2023-08-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	1004029-8
ISSN	1098-2744 ; 0899-1987
ISSN (online)	1098-2744
ISSN	0899-1987
DOI	10.1002/mc.23616
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Article ; Online: ERBB3 Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature.

Vellky, Jordan E / Kirkpatrick, Brenna J / Gutgesell, Lisa C / Morales, Mathias / Brown, Ryan M / Wu, Yaqi / Maienschein-Cline, Mark / Notardonato, Lucia D / Weinfeld, Michael S / Nguyen, Ryan H / Brister, Eileen / Sverdlov, Maria / Liu, Li / Xu, Ziqiao / Kregel, Steven / Nonn, Larisa / Vander Griend, Donald J / Reizine, Natalie M

Clinical cancer research : an official journal of the American Association for Cancer Research

2024 Volume 30, Issue 8, Page(s) 1530–1543

Abstract: Purpose: Despite successful clinical management of castration-sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer is only 32%. Combination treatment strategies to prevent disease recurrence are ... ...

Abstract	Purpose: Despite successful clinical management of castration-sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer is only 32%. Combination treatment strategies to prevent disease recurrence are increasing, albeit in biomarker-unselected patients. Identifying a biomarker in CSPC to stratify patients who will progress on standard-of-care therapy could guide therapeutic strategies. Experimental design: Targeted deep sequencing was performed for the University of Illinois (UI) cohort (n = 30), and immunostaining was performed on a patient tissue microarray (n = 149). Bioinformatic analyses identified pathways associated with biomarker overexpression (OE) in the UI cohort, consolidated RNA sequencing samples accessed from Database of Genotypes and Phenotypes (n = 664), and GSE209954 (n = 68). Neutralizing antibody patritumab and ectopic HER3 OE were utilized for functional mechanistic experiments. Results: We identified ERBB3 OE in diverse patient populations with CSPC, where it was associated with advanced disease at diagnosis. Bioinformatic analyses showed a positive correlation between ERBB3 expression and the androgen response pathway despite low dihydrotestosterone and stable expression of androgen receptor (AR) transcript in Black/African American men. At the protein level, HER3 expression was negatively correlated with intraprostatic androgen in Black/African American men. Mechanistically, HER3 promoted enzalutamide resistance in prostate cancer cell line models and HER3-targeted therapy resensitized therapy-resistant prostate cancer cell lines to enzalutamide. Conclusions: In diverse patient populations with CSPC, ERBB3 OE was associated with high AR signaling despite low intraprostatic androgen. Mechanistic studies demonstrated a direct link between HER3 and enzalutamide resistance. ERBB3 OE as a biomarker could thus stratify patients for intensification of therapy in castration-sensitive disease, including targeting HER3 directly to improve sensitivity to AR-targeted therapies.
MeSH term(s)	Male ; Humans ; Prostatic Neoplasms, Castration-Resistant/drug therapy ; Prostatic Neoplasms, Castration-Resistant/genetics ; Prostatic Neoplasms, Castration-Resistant/metabolism ; Androgens/therapeutic use ; Neoplasm Recurrence, Local ; Receptors, Androgen/genetics ; Receptors, Androgen/metabolism ; Nitriles/therapeutic use ; Biomarkers ; Castration ; Drug Resistance, Neoplasm/genetics ; Cell Line, Tumor ; Receptor, ErbB-3/genetics ; Benzamides ; Phenylthiohydantoin
Chemical Substances	enzalutamide (93T0T9GKNU) ; Androgens ; Receptors, Androgen ; Nitriles ; Biomarkers ; ERBB3 protein, human (EC 2.7.10.1) ; Receptor, ErbB-3 (EC 2.7.10.1) ; Benzamides ; Phenylthiohydantoin (2010-15-3)
Language	English
Publishing date	2024-02-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-23-2161
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Zs.A 4223: Show issues

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Article ; Online: C-type lectin receptor expression is a hallmark of neutrophils infiltrating the skin in epidermolysis bullosa acquisita.

Guerrero-Juarez, Christian F / Schilf, Paul / Li, Jing / Zappia, Maria Paula / Bao, Lei / Patel, Payal M / Gieseler-Tillmann, Jenny / Murthy, Sripriya / Cole, Connor / Sverdlov, Maria / Frolov, Maxim V / Hashimoto, Takashi / Ishii, Norito / Rülicke, Thomas / Bieber, Katja / Ludwig, Ralf J / Sadik, Christian D / Amber, Kyle T

Frontiers in immunology

2023 Volume 14, Page(s) 1266359

Abstract: Introduction: Inflammatory epidermolysis bullosa acquisita (EBA) is characterized by a neutrophilic response to anti-type VII collagen (COL7) antibodies resulting in the development of skin inflammation and blistering. The antibody transfer model of EBA ...

Abstract	Introduction: Inflammatory epidermolysis bullosa acquisita (EBA) is characterized by a neutrophilic response to anti-type VII collagen (COL7) antibodies resulting in the development of skin inflammation and blistering. The antibody transfer model of EBA closely mirrors this EBA phenotype. Methods: To better understand the changes induced in neutrophils upon recruitment from peripheral blood into lesional skin in EBA, we performed single-cell RNA-sequencing of whole blood and skin dissociate to capture minimally perturbed neutrophils and characterize their transcriptome. Results: Through this approach, we identified clear distinctions between circulating activated neutrophils and intradermal neutrophils. Most strikingly, the gene expression of multiple C-type lectin receptors, which have previously been reported to orchestrate host defense against fungi and select bacteria, were markedly dysregulated. After confirming the upregulation of Discussion: Collectively, our results suggest that while the upregulation of
MeSH term(s)	Humans ; Animals ; Mice ; Epidermolysis Bullosa Acquisita ; Neutrophils ; Autoantibodies ; Skin ; Blister
Chemical Substances	Autoantibodies
Language	English
Publishing date	2023-09-20
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1266359
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Article ; Online: Inhibition of CCL28/CCR10-Mediated eNOS Downregulation Improves Skin Wound Healing in the Obesity-Induced Mouse Model of Type 2 Diabetes.

Chen, Zhenlong / Haus, Jacob M / Chen, Lin / Jiang, Ying / Sverdlov, Maria / DiPietro, Luisa A / Xiong, Na / Wu, Stephanie C / Koh, Timothy J / Minshall, Richard D

Diabetes

2022 Volume 71, Issue 10, Page(s) 2166–2180

Abstract: Chronic, nonhealing skin wounds, such as diabetic foot ulcers (DFUs), are common in patients with type 2 diabetes. Here, we investigated the role of chemokine (C-C motif) ligand 28 (CCL28) and its receptor C-C chemokine receptor type 10 (CCR10) in ... ...

Abstract	Chronic, nonhealing skin wounds, such as diabetic foot ulcers (DFUs), are common in patients with type 2 diabetes. Here, we investigated the role of chemokine (C-C motif) ligand 28 (CCL28) and its receptor C-C chemokine receptor type 10 (CCR10) in downregulation of endothelial nitric (NO) oxide synthase (eNOS) in association with delayed skin wound healing in the db/db mouse model of type 2 diabetes. We observed reduced eNOS expression and elevated CCL28/CCR10 levels in dorsal skin of db/db mice and subdermal leg biopsy specimens from human subjects with type 2 diabetes. Further interrogation revealed that overexpression of CCR10 reduced eNOS expression, NO bioavailability, and tube formation of human dermal microvascular endothelial cells (HDMVECs) in vitro, which was recapitulated in mouse dorsal skin. In addition, incubation of HDMVECs with CCL28 led to internalization of the CCR10/eNOS complex and colocalization with lysosome-associated membrane protein 1. Finally, topical application of myristoylated CCR10 binding domain 7 amino acid (Myr-CBD7) peptide prevented CCR10-eNOS interaction and subsequent eNOS downregulation, enhanced eNOS/NO levels, eNOS/VEGF-R2+ microvessel density, and blood perfusion, reduced inflammatory cytokine levels, and importantly, decreased wound healing time in db/db mice. Thus, endothelial cell CCR10 activation in genetically obese mice with type 2 diabetes promotes eNOS depletion and endothelial dysfunction, and targeted disruption of CCR10/eNOS interaction improves wound healing.
MeSH term(s)	Amino Acids/metabolism ; Animals ; Chemokines/metabolism ; Chemokines, CC ; Diabetes Mellitus, Type 2/complications ; Disease Models, Animal ; Down-Regulation ; Endothelial Cells/metabolism ; Humans ; Ligands ; Lysosomal Membrane Proteins/metabolism ; Mice ; Nitric Oxide Synthase Type III/genetics ; Nitric Oxide Synthase Type III/metabolism ; Obesity/genetics ; Oxides/metabolism ; Receptors, CCR10 ; Receptors, Chemokine/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Wound Healing
Chemical Substances	Amino Acids ; CCL28 protein, human ; CCR10 protein, human ; Ccl28 protein, mouse ; Chemokines ; Chemokines, CC ; Ligands ; Lysosomal Membrane Proteins ; Oxides ; Receptors, CCR10 ; Receptors, Chemokine ; Vascular Endothelial Growth Factor A ; Nitric Oxide Synthase Type III (EC 1.14.13.39)
Language	English
Publishing date	2022-07-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db21-1108
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Article ; Online: The basis and design for time-restricted eating compared with daily calorie restriction for weight loss and colorectal cancer risk reduction trial (TRE-CRC trial).

Gabel, Kelsey / Fitzgibbon, Marian L / Yazici, Cemal / Gann, Peter / Sverdlov, Maria / Guzman, Grace / Chen, Zhengjia / McLeod, Andrew / Hamm, Alyshia / Varady, Krista A / Tussing-Humphreys, Lisa

Obesity (Silver Spring, Md.)

2022 Volume 30, Issue 12, Page(s) 2376–2385

Abstract: Objective: Approximately 42% of American adults are living with obesity, increasing their risk of colorectal cancer (CRC). Efficacious approaches to prevent and treat obesity may reduce CRC incidence. Daily calorie restriction (Cal-R) is the most common ...

Abstract	Objective: Approximately 42% of American adults are living with obesity, increasing their risk of colorectal cancer (CRC). Efficacious approaches to prevent and treat obesity may reduce CRC incidence. Daily calorie restriction (Cal-R) is the most common approach to treating obesity, yet clinically meaningful weight loss is elusive owing to waning adherence. Time-restricted eating (TRE) consists of consuming foods within a specified time frame, creating a natural calorie deficit. TRE in animals shows cancer protective effects. In humans, TRE is safe and acceptable among adults with obesity, producing ~3% to 5% weight loss and reductions in oxidative stress and insulin resistance. However, TRE has not been tested rigorously for CRC preventive effects. Methods: The authors describe a 12-month randomized controlled trial of 8-hour TRE (ad libitum 12 PM-8 PM), Cal-R (25% restriction daily), or Control among 255 adults at increased risk for CRC and with obesity. Results: Effects on the following will be examined: 1) body weight, body composition, and adherence; 2) circulating metabolic, inflammation, and oxidative stress biomarkers; 3) colonic mucosal gene expression profiles and tissue microenvironment; and 4) maintenance of benefits on body weight/composition and CRC risk markers. Conclusions: This study will examine efficacious lifestyle strategies to treat obesity and reduce CRC risk among individuals with obesity.
MeSH term(s)	Adult ; Animals ; Humans ; Caloric Restriction ; Weight Loss ; Obesity/therapy ; Risk Reduction Behavior ; Colorectal Neoplasms/prevention & control ; Fasting ; Tumor Microenvironment
Language	English
Publishing date	2022-11-01
Publishing country	United States
Document type	Randomized Controlled Trial ; Journal Article
ZDB-ID	2230457-5
ISSN	1930-739X ; 1071-7323 ; 1930-7381
ISSN (online)	1930-739X
ISSN	1071-7323 ; 1930-7381
DOI	10.1002/oby.23579
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Zs.A 4061: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Targeting Lymphoma-associated Macrophage Expansion via CSF1R/JAK Inhibition is a Therapeutic Vulnerability in Peripheral T-cell Lymphomas.

Gao, Xin / Kady, Nermin / Wang, Chenguang / Abdelrahman, Suhaib / Gann, Peter / Sverdlov, Maria / Wolfe, Ashley / Brown, Noah / Reneau, John / Robida, Aaron M / Murga-Zamalloa, Carlos / Wilcox, Ryan A

Cancer research communications

2022 Volume 2, Issue 12, Page(s) 1727–1737

Abstract: The reciprocal relationship between malignant T cells and lymphoma-associated macrophages (LAM) within the tumor microenvironment (TME) is unique, as LAMs are well poised to provide ligands for antigen, costimulatory, and cytokine receptors that promote ... ...

Abstract	The reciprocal relationship between malignant T cells and lymphoma-associated macrophages (LAM) within the tumor microenvironment (TME) is unique, as LAMs are well poised to provide ligands for antigen, costimulatory, and cytokine receptors that promote T-cell lymphoma growth. Conversely, malignant T cells promote the functional polarization and homeostatic survival of LAM. Therefore, we sought to determine the extent to which LAMs are a therapeutic vulnerability in these lymphomas, and to identify effective therapeutic strategies for their depletion. We utilized complementary genetically engineered mouse models and primary peripheral T-cell lymphoma (PTCL) specimens to quantify LAM expansion and proliferation. A high-throughput screen was performed to identify targeted agents that effectively deplete LAM within the context of PTCL. We observed that LAMs are dominant constituents of the TME in PTCL. Furthermore, their dominance was explained, at least in part, by their proliferation and expansion in response to PTCL-derived cytokines. Importantly, LAMs are a true dependency in these lymphomas, as their depletion significantly impaired PTCL progression. These findings were extrapolated to a large cohort of human PTCL specimens where LAM proliferation was observed. A high-throughput screen demonstrated that PTCL-derived cytokines led to relative resistance to CSF1R selective inhibitors, and culminated in the identification of dual CSF1R/JAK inhibition as a novel therapeutic strategy to deplete LAM in these aggressive lymphomas. Malignant T cells promote the expansion and proliferation of LAM, which are a Significance: LAMs are a therapeutic vulnerability, as their depletion impairs T-cell lymphoma disease progression. Pacritinib, a dual CSF1R/JAK inhibitor, effectively impaired LAM viability and expansion, prolonged survival in preclinical T-cell lymphoma models, and is currently being investigated as a novel therapeutic approach in these lymphomas.
MeSH term(s)	Animals ; Mice ; Humans ; Lymphoma, T-Cell, Peripheral/drug therapy ; Janus Kinase Inhibitors/pharmacology ; Cytokines/pharmacology ; Lymphoma, T-Cell/drug therapy ; Macrophages ; Tumor Microenvironment
Chemical Substances	Janus Kinase Inhibitors ; Cytokines
Language	English
Publishing date	2022-12-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2767-9764
ISSN (online)	2767-9764
DOI	10.1158/2767-9764.CRC-22-0336
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Article ; Online: Specific Polo-Like Kinase 1 Expression in Nodular Lymphocyte-Predominant Hodgkin Lymphoma Suggests an Intact Immune Surveillance Program.

The American journal of pathology

2023 Volume 194, Issue 1, Page(s) 165–178

Abstract: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare and relatively indolent B-cell lymphoma. Characteristically, the [lymphocyte-predominant (LP)] tumor cells are embedded in a microenvironment enriched in lymphocytes. More aggressive ... ...

Abstract	Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare and relatively indolent B-cell lymphoma. Characteristically, the [lymphocyte-predominant (LP)] tumor cells are embedded in a microenvironment enriched in lymphocytes. More aggressive variants of mature B-cell and peripheral T-cell lymphomas exhibit nuclear expression of the polo-like kinase 1 (PLK1) protein, stabilizing MYC (alias c-myc) and associated with worse clinical outcomes. This study demonstrated expression of PLK1 in the LP cells in 100% of NLPHL cases (n = 76). In contrast, <5% of classic Hodgkin lymphoma cases (n = 70) showed PLK1 expression within the tumor cells. Loss-of-function approaches demonstrated that the expression of PLK1 promoted cell proliferation and increased MYC stability in NLPHL cell lines. Correlation with clinical parameters revealed that the increased expression of PLK1 was associated with advanced-stage disease in patients with NLPHL. A multiplex immunofluorescence panel coupled with artificial intelligence algorithms was used to correlate the composition of the tumor microenvironment with the proliferative stage of LP cells. The results showed that LP cells with PLK1 (high) expression were associated with increased numbers of cytotoxic and T-regulatory T cells. Overall, the findings demonstrate that PLK1 signaling increases NLPHL proliferation and constitutes a potential vulnerability that can be targeted with PLK1 inhibitors. An active immune surveillance program in NLPHL may be a critical mechanism limiting PLK1-dependent tumor growth.
MeSH term(s)	Humans ; Artificial Intelligence ; Hodgkin Disease/metabolism ; Hodgkin Disease/pathology ; Lymphocytes/pathology ; Lymphoma, B-Cell/pathology ; Polo-Like Kinase 1 ; Tumor Microenvironment
Chemical Substances	Polo-Like Kinase 1 ; PLK1 protein, human
Language	English
Publishing date	2023-11-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2023.10.008
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