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Article ; Online: Single-Cell Characterization of the Tumor Ecosystem in Liver Cancer.

Wang, Limin / Revsine, Mahler / Wang, Xin Wei / Ma, Lichun

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

2024 Volume 2769, Page(s) 153–166

Abstract: Tumor heterogeneity along with the complex landscape of the tumor microenvironment create critical challenges for effective liver cancer interventions. Characterizing the tumor ecosystem at the single-cell level may provide insight into the collective ... ...

Abstract	Tumor heterogeneity along with the complex landscape of the tumor microenvironment create critical challenges for effective liver cancer interventions. Characterizing the tumor ecosystem at the single-cell level may provide insight into the collective behaviors of tumor cells and their interplays with stromal and immune cells. Here we introduce the experimental protocol and computational methods for the single-cell study of liver cancer, which may be essential for a mechanistic understanding of the tumor ecosystem in liver cancer and further pave the way for developing novel therapeutics.
MeSH term(s)	Humans ; Carcinoma, Hepatocellular/pathology ; Liver Neoplasms/pathology ; Tumor Microenvironment
Language	English
Publishing date	2024-02-05
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-3694-7_12
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Lineage and ecology define liver tumor evolution in response to treatment.

Revsine, Mahler / Wang, Limin / Forgues, Marshonna / Behrens, Shay / Craig, Amanda J / Liu, Meng / Tran, Bao / Kelly, Michael / Budhu, Anuradha / Monge, Cecilia / Xie, Changqing / Hernandez, Jonathan M / Greten, Tim F / Wang, Xin Wei / Ma, Lichun

Cell reports. Medicine

2024 Volume 5, Issue 2, Page(s) 101394

Abstract: A tumor ecosystem constantly evolves over time in the face of immune predation or therapeutic intervention, resulting in treatment failure and tumor progression. Here, we present a single-cell transcriptome-based strategy to determine the evolution of ... ...

Abstract	A tumor ecosystem constantly evolves over time in the face of immune predation or therapeutic intervention, resulting in treatment failure and tumor progression. Here, we present a single-cell transcriptome-based strategy to determine the evolution of longitudinal tumor biopsies from liver cancer patients by measuring cellular lineage and ecology. We construct a lineage and ecological score as joint dynamics of tumor cells and their microenvironments. Tumors may be classified into four main states in the lineage-ecological space, which are associated with clinical outcomes. Analysis of longitudinal samples reveals the evolutionary trajectory of tumors in response to treatment. We validate the lineage-ecology-based scoring system in predicting clinical outcomes using bulk transcriptomic data of additional cohorts of 716 liver cancer patients. Our study provides a framework for monitoring tumor evolution in response to therapeutic intervention.
MeSH term(s)	Humans ; Cell Lineage/genetics ; Gene Expression Profiling ; Liver Neoplasms/genetics ; Liver Neoplasms/therapy ; Liver Neoplasms/pathology ; Transcriptome/genetics ; Tumor Microenvironment/genetics
Language	English
Publishing date	2024-01-26
Publishing country	United States
Document type	Journal Article
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2024.101394
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Article ; Online: Immunosuppressive CD29

Gut

2024 Volume 73, Issue 3, Page(s) 509–520

Abstract: Objective: Liver metastases are often resistant to immune checkpoint inhibitor therapy (ICI) and portend a worse prognosis compared with metastases to other locations. Regulatory T cells (Tregs) are one of several immunosuppressive cells implicated in ... ...

Abstract	Objective: Liver metastases are often resistant to immune checkpoint inhibitor therapy (ICI) and portend a worse prognosis compared with metastases to other locations. Regulatory T cells (Tregs) are one of several immunosuppressive cells implicated in ICI resistance of liver tumours, but the role played by Tregs residing within the liver surrounding a tumour is unknown. Design: Flow cytometry and single-cell RNA sequencing were used to characterise hepatic Tregs before and after ICI therapy. Results: We found that the murine liver houses a Treg population that, unlike those found in other organs, is both highly proliferative and apoptotic at baseline. On administration of αPD-1, αPD-L1 or αCTLA4, the liver Treg population doubled regardless of the presence of an intrahepatic tumour. Remarkably, this change was not due to the preferential expansion of the subpopulation of Tregs that express PD-1. Instead, a subpopulation of CD29 Conclusion: We propose that CD29
MeSH term(s)	Animals ; Mice ; T-Lymphocytes, Regulatory ; Interleukin-2 ; Integrin beta1 ; Liver Neoplasms/drug therapy ; Liver Neoplasms/pathology
Chemical Substances	Interleukin-2 ; Integrin beta1
Language	English
Publishing date	2024-02-23
Publishing country	England
Document type	Journal Article
ZDB-ID	80128-8
ISSN	1468-3288 ; 0017-5749
ISSN (online)	1468-3288
ISSN	0017-5749
DOI	10.1136/gutjnl-2023-330024
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Article ; Online: Acute Leukemia Classification Using Transcriptional Profiles From Low-Cost Nanopore mRNA Sequencing.

Wang, Jeremy / Bhakta, Nickhill / Ayer Miller, Vanessa / Revsine, Mahler / Litzow, Mark R / Paietta, Elisabeth / Fedoriw, Yuri / Roberts, Kathryn G / Gu, Zhaohui / Mullighan, Charles G / Jones, Corbin D / Alexander, Thomas B

JCO precision oncology

2022 Volume 6, Page(s) e2100326

Abstract: Purpose: Most cases of pediatric acute leukemia occur in low- and middle-income countries, where health centers lack the tools required for accurate diagnosis and disease classification. Recent research shows the robustness of using unbiased short-read ... ...

Abstract	Purpose: Most cases of pediatric acute leukemia occur in low- and middle-income countries, where health centers lack the tools required for accurate diagnosis and disease classification. Recent research shows the robustness of using unbiased short-read RNA sequencing to classify genomic subtypes of acute leukemia. Compared with short-read sequencing, nanopore sequencing has low capital and consumable costs, making it suitable for use in locations with limited health infrastructure. Materials and methods: We show the feasibility of nanopore mRNA sequencing on 134 cryopreserved acute leukemia specimens (26 acute myeloid leukemia [AML], 73 B-lineage acute lymphoblastic leukemia [B-ALL], 34 T-lineage acute lymphoblastic leukemia, and one acute undifferentiated leukemia). Using multiple library preparation approaches, we generated long-read transcripts for each sample. We developed a novel composite classification approach to predict acute leukemia lineage and major B-ALL and AML molecular subtypes directly from gene expression profiles. Results: We demonstrate accurate classification of acute leukemia samples into AML, B-ALL, or T-lineage acute lymphoblastic leukemia (96.2% of cases are classifiable with a probability of > 0.8, with 100% accuracy) and further classification into clinically actionable genomic subtypes using shallow RNA nanopore sequencing, with 96.2% accuracy for major AML subtypes and 94.1% accuracy for major B-lineage acute lymphoblastic leukemia subtypes. Conclusion: Transcriptional profiling of acute leukemia samples using nanopore technology for diagnostic classification is feasible and accurate, which has the potential to improve the accuracy of cancer diagnosis in low-resource settings.
MeSH term(s)	Acute Disease ; Child ; Humans ; Leukemia, Myeloid, Acute/diagnosis ; Nanopore Sequencing ; Nanopores ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis ; RNA, Messenger/genetics
Chemical Substances	RNA, Messenger
Language	English
Publishing date	2022-04-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2473-4284
ISSN (online)	2473-4284
DOI	10.1200/PO.21.00326
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Article ; Online: Genome-wide profiling of transcription factor activity in primary liver cancer using single-cell ATAC sequencing.

Craig, Amanda J / Silveira, Maruhen A Datsch / Ma, Lichun / Revsine, Mahler / Wang, Limin / Heinrich, Sophia / Rae, Zachary / Ruchinskas, Allison / Dadkhah, Kimia / Do, Whitney / Behrens, Shay / Mehrabadi, Farid R / Dominguez, Dana A / Forgues, Marshonna / Budhu, Anuradha / Chaisaingmongkol, Jittiporn / Hernandez, Jonathan M / Davis, Jeremy L / Tran, Bao /

Marquardt, Jens U / Ruchirawat, Mathuros / Kelly, Michael / Greten, Tim F / Wang, Xin W

Cell reports

2023 Volume 42, Issue 11, Page(s) 113446

Abstract: Primary liver cancer (PLC) consists of two main histological subtypes; hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). The role of transcription factors (TFs) in malignant hepatobiliary lineage commitment between HCC and iCCA ... ...

Abstract	Primary liver cancer (PLC) consists of two main histological subtypes; hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). The role of transcription factors (TFs) in malignant hepatobiliary lineage commitment between HCC and iCCA remains underexplored. Here, we present genome-wide profiling of transcription regulatory elements of 16 PLC patients using single-cell assay for transposase accessible chromatin sequencing. Single-cell open chromatin profiles reflect the compositional diversity of liver cancer, identifying both malignant and microenvironment component cells. TF motif enrichment levels of 31 TFs strongly discriminate HCC from iCCA tumors. These TFs are members of the nuclear/retinoid receptor, POU, or ETS motif families. POU factors are associated with prognostic features in iCCA. Overall, nuclear receptors, ETS and POU TF motif families delineate transcription regulation between HCC and iCCA tumors, which may be relevant to development and selection of PLC subtype-specific therapeutics.
MeSH term(s)	Humans ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Cholangiocarcinoma/genetics ; Cholangiocarcinoma/pathology ; Transcription Factors/genetics ; Bile Ducts, Intrahepatic/pathology ; Bile Duct Neoplasms/pathology ; Chromatin ; Tumor Microenvironment
Chemical Substances	Transcription Factors ; Chromatin
Language	English
Publishing date	2023-11-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.113446
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Article ; Online: Tumor biology and immune infiltration define primary liver cancer subsets linked to overall survival after immunotherapy.

Budhu, Anuradha / Pehrsson, Erica C / He, Aiwu / Goyal, Lipika / Kelley, Robin Kate / Dang, Hien / Xie, Changqing / Monge, Cecilia / Tandon, Mayank / Ma, Lichun / Revsine, Mahler / Kuhlman, Laura / Zhang, Karen / Baiev, Islam / Lamm, Ryan / Patel, Keyur / Kleiner, David E / Hewitt, Stephen M / Tran, Bao /

Shetty, Jyoti / Wu, Xiaolin / Zhao, Yongmei / Shen, Tsai-Wei / Choudhari, Sulbha / Kriga, Yuliya / Ylaya, Kris / Warner, Andrew C / Edmondson, Elijah F / Forgues, Marshonna / Greten, Tim F / Wang, Xin Wei

Cell reports. Medicine

2023 Volume 4, Issue 6, Page(s) 101052

Abstract: Primary liver cancer is a rising cause of cancer deaths in the US. Although immunotherapy with immune checkpoint inhibitors induces a potent response in a subset of patients, response rates vary among individuals. Predicting which patients will respond ... ...

Abstract	Primary liver cancer is a rising cause of cancer deaths in the US. Although immunotherapy with immune checkpoint inhibitors induces a potent response in a subset of patients, response rates vary among individuals. Predicting which patients will respond to immune checkpoint inhibitors is of great interest in the field. In a retrospective arm of the National Cancer Institute Cancers of the Liver: Accelerating Research of Immunotherapy by a Transdisciplinary Network (NCI-CLARITY) study, we use archived formalin-fixed, paraffin-embedded samples to profile the transcriptome and genomic alterations among 86 hepatocellular carcinoma and cholangiocarcinoma patients prior to and following immune checkpoint inhibitor treatment. Using supervised and unsupervised approaches, we identify stable molecular subtypes linked to overall survival and distinguished by two axes of aggressive tumor biology and microenvironmental features. Moreover, molecular responses to immune checkpoint inhibitor treatment differ between subtypes. Thus, patients with heterogeneous liver cancer may be stratified by molecular status indicative of treatment response to immune checkpoint inhibitors.
MeSH term(s)	Humans ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Retrospective Studies ; Immunotherapy ; Carcinoma, Hepatocellular/therapy ; Liver Neoplasms/therapy ; Genomics
Chemical Substances	Immune Checkpoint Inhibitors
Language	English
Publishing date	2023-05-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2023.101052
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Nanopore sequencing of 1000 Genomes Project samples to build a comprehensive catalog of human genetic variation.

Gustafson, Jonas A / Gibson, Sophia B / Damaraju, Nikhita / Zalusky, Miranda Pg / Hoekzema, Kendra / Twesigomwe, David / Yang, Lei / Snead, Anthony A / Richmond, Phillip A / De Coster, Wouter / Olson, Nathan D / Guarracino, Andrea / Li, Qiuhui / Miller, Angela L / Goffena, Joy / Anderson, Zachery / Storz, Sophie Hr / Ward, Sydney A / Sinha, Maisha /

Gonzaga-Jauregui, Claudia / Clarke, Wayne E / Basile, Anna O / Corvelo, André / Reeves, Catherine / Helland, Adrienne / Musunuri, Rajeeva Lochan / Revsine, Mahler / Patterson, Karynne E / Paschal, Cate R / Zakarian, Christina / Goodwin, Sara / Jensen, Tanner D / Robb, Esther / McCombie, W Richard / Sedlazeck, Fritz J / Zook, Justin M / Montgomery, Stephen B / Garrison, Erik / Kolmogorov, Mikhail / Schatz, Michael C / McLaughlin, Richard N / Dashnow, Harriet / Zody, Michael C / Loose, Matt / Jain, Miten / Eichler, Evan E / Miller, Danny E

medRxiv : the preprint server for health sciences

2024

Abstract: Less than half of individuals with a suspected Mendelian condition receive a precise molecular diagnosis after comprehensive clinical genetic testing. Improvements in data quality and costs have heightened interest in using long-read sequencing (LRS) to ... ...

Abstract	Less than half of individuals with a suspected Mendelian condition receive a precise molecular diagnosis after comprehensive clinical genetic testing. Improvements in data quality and costs have heightened interest in using long-read sequencing (LRS) to streamline clinical genomic testing, but the absence of control datasets for variant filtering and prioritization has made tertiary analysis of LRS data challenging. To address this, the 1000 Genomes Project ONT Sequencing Consortium aims to generate LRS data from at least 800 of the 1000 Genomes Project samples. Our goal is to use LRS to identify a broader spectrum of variation so we may improve our understanding of normal patterns of human variation. Here, we present data from analysis of the first 100 samples, representing all 5 superpopulations and 19 subpopulations. These samples, sequenced to an average depth of coverage of 37x and sequence read N50 of 54 kbp, have high concordance with previous studies for identifying single nucleotide and indel variants outside of homopolymer regions. Using multiple structural variant (SV) callers, we identify an average of 24,543 high-confidence SVs per genome, including shared and private SVs likely to disrupt gene function as well as pathogenic expansions within disease-associated repeats that were not detected using short reads. Evaluation of methylation signatures revealed expected patterns at known imprinted loci, samples with skewed X-inactivation patterns, and novel differentially methylated regions. All raw sequencing data, processed data, and summary statistics are publicly available, providing a valuable resource for the clinical genetics community to discover pathogenic SVs.
Language	English
Publishing date	2024-03-07
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.05.24303792
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Article ; Online: Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin.

Ruf, Benjamin / Bruhns, Matthias / Babaei, Sepideh / Kedei, Noemi / Ma, Lichun / Revsine, Mahler / Benmebarek, Mohamed-Reda / Ma, Chi / Heinrich, Bernd / Subramanyam, Varun / Qi, Jonathan / Wabitsch, Simon / Green, Benjamin L / Bauer, Kylynda C / Myojin, Yuta / Greten, Layla T / McCallen, Justin D / Huang, Patrick / Trehan, Rajiv /

Wang, Xin / Nur, Amran / Murphy Soika, Dana Qiang / Pouzolles, Marie / Evans, Christine N / Chari, Raj / Kleiner, David E / Telford, William / Dadkhah, Kimia / Ruchinskas, Allison / Stovroff, Merrill K / Kang, Jiman / Oza, Kesha / Ruchirawat, Mathuros / Kroemer, Alexander / Wang, Xin Wei / Claassen, Manfred / Korangy, Firouzeh / Greten, Tim F

Cell

2023 Volume 186, Issue 17, Page(s) 3686–3705.e32

Abstract: Mucosal-associated invariant T (MAIT) cells represent an abundant innate-like T cell subtype in the human liver. MAIT cells are assigned crucial roles in regulating immunity and inflammation, yet their role in liver cancer remains elusive. Here, we ... ...

Abstract	Mucosal-associated invariant T (MAIT) cells represent an abundant innate-like T cell subtype in the human liver. MAIT cells are assigned crucial roles in regulating immunity and inflammation, yet their role in liver cancer remains elusive. Here, we present a MAIT cell-centered profiling of hepatocellular carcinoma (HCC) using scRNA-seq, flow cytometry, and co-detection by indexing (CODEX) imaging of paired patient samples. These analyses highlight the heterogeneity and dysfunctionality of MAIT cells in HCC and their defective capacity to infiltrate liver tumors. Machine-learning tools were used to dissect the spatial cellular interaction network within the MAIT cell neighborhood. Co-localization in the adjacent liver and interaction between niche-occupying CSF1R
MeSH term(s)	Animals ; Humans ; Mice ; Carcinoma, Hepatocellular/immunology ; Carcinoma, Hepatocellular/pathology ; Liver Neoplasms/immunology ; Liver Neoplasms/pathology ; Mucosal-Associated Invariant T Cells/immunology ; Mucosal-Associated Invariant T Cells/pathology ; Tumor-Associated Macrophages
Language	English
Publishing date	2023-08-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2023.07.026
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Zs.MG 58: Show issues

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Article ; Online: Single-Cell Characterization of the Tumor Ecosystem in Liver Cancer.

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Article ; Online: Lineage and ecology define liver tumor evolution in response to treatment.

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Article ; Online: Immunosuppressive CD29

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Article ; Online: Acute Leukemia Classification Using Transcriptional Profiles From Low-Cost Nanopore mRNA Sequencing.

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Article ; Online: Genome-wide profiling of transcription factor activity in primary liver cancer using single-cell ATAC sequencing.

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Article ; Online: Tumor biology and immune infiltration define primary liver cancer subsets linked to overall survival after immunotherapy.

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Article: Nanopore sequencing of 1000 Genomes Project samples to build a comprehensive catalog of human genetic variation.

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Article ; Online: Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin.

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