Publications by authors named "Amaia Lujambio"

54 Publications

Diverse immune response of DNA damage repair-deficient tumors.

Cell Rep Med 2021 May 18;2(5):100276. Epub 2021 May 18.

Department of Genetics and Genomic Sciences, Center for Transformative Disease Modeling, Tisch Cancer Institute, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Tumors with DNA damage repair (DDR) deficiency accumulate genomic alterations that may serve as neoantigens and increase sensitivity to immune checkpoint inhibitor. However, over half of DDR-deficient tumors are refractory to immunotherapy, and it remains unclear which mutations may promote immunogenicity in which cancer types. We integrate deleterious somatic and germline mutations and methylation data of DDR genes in 10,080 cancers representing 32 cancer types and evaluate the associations of these alterations with tumor neoantigens and immune infiltrates. Our analyses identify DDR pathway mutations that are associated with higher neoantigen loads, adaptive immune markers, and survival outcomes of immune checkpoint inhibitor-treated animal models and patients. Different immune phenotypes are associated with distinct types of DDR deficiency, depending on the cancer type context. The comprehensive catalog of immune response-associated DDR deficiency may explain variations in immunotherapy outcomes across DDR-deficient cancers and facilitate the development of genomic biomarkers for immunotherapy.
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http://dx.doi.org/10.1016/j.xcrm.2021.100276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149377PMC
May 2021

The Endless Sources of Hepatocellular Carcinoma Heterogeneity.

Cancers (Basel) 2021 May 26;13(11). Epub 2021 May 26.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Hepatocellular carcinoma (HCC) represents a global health problem. The incidence keeps increasing and current therapeutic options confer limited benefits to the patients. Tumor heterogeneity plays a central role in this context, limiting the availability of predictive biomarkers and complicating the criteria used to choose the most suitable therapeutic option. HCC heterogeneity occurs at different levels: within the population (inter-patient heterogeneity) and within tumors from the same patient (intra-patient and intra-tumor heterogeneity). Experts in the field have made many efforts to classify the patients based on clinicopathological characteristics and molecular signatures; however, there is still much work ahead to be able to integrate the extra-tumor heterogeneity that emerges from the complexity of the tumor microenvironment, which plays a critical role in the pathogenesis of the disease and therapy responses. In this review, we summarize tumor intrinsic and extrinsic sources of heterogeneity of the most common etiologies of HCC and summarize the most recent discoveries regarding the evolutionary trajectory of liver cancer cells and the influence of tumor-extrinsic factors such as the microbiome and the host immune system. We further highlight the potential of novel high-throughput methodologies to contribute to a better understanding of this devastating disease and to the improvement of the clinical management of patients.
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http://dx.doi.org/10.3390/cancers13112621DOI Listing
May 2021

Dissecting early relapse in liver cancer, one cell at a time.

Hepatology 2021 May 17. Epub 2021 May 17.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

In a recent issue of Cell, Sun Y, Wu L, Zhong Y, et al. Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma. Cell 2021;184:404-421 e416, performed single-cell RNA sequencing (scRNAseq) to study the underlying mechanisms associated with the recurrence of hepatocellular carcinoma (HCC) and address this unmet clinical need (1). The analysis included tumors from 12 treatment-naïve primary liver cancer patients, 6 early-relapsed patients, and 4 patients with paired primary and early-relapsed tumors.
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http://dx.doi.org/10.1002/hep.31903DOI Listing
May 2021

Tumor-Intrinsic Mechanisms Regulating Immune Exclusion in Liver Cancers.

Front Immunol 2021 26;12:642958. Epub 2021 Apr 26.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Representing the fourth leading cause of cancer-related mortality worldwide, liver cancers constitute a major global health concern. Hepatocellular carcinoma (HCC), the most frequent type of liver cancer, is associated with dismal survival outcomes and has traditionally had few treatment options available. In fact, up until 2017, treatment options for advanced HCC were restricted to broad acting tyrosine kinase inhibitors, including Sorafenib, which has been the standard of care for over a decade. Since 2017, a multitude of mono- and combination immunotherapies that include pembrolizumab, nivolumab, ipilumumab, atezolizumab, and bevacizumab have been FDA-approved for the treatment of advanced HCC with unprecedented response rates ranging from 20 to 30% of patients. However, this also means that ~70% of patients do not respond to this treatment and currently very little is known regarding mechanisms of action of these immunotherapies as well as predictors of response to facilitate patient stratification. With the recent success of immunotherapies in HCC, there is a pressing need to understand mechanisms of tumor immune evasion and resistance to these immunotherapies in order to identify biomarkers of resistance or response. This will enable better patient stratification as well as the rational design of combination immunotherapies to restore sensitivity in resistant patients. The aim of this review is to summarize the current knowledge to date of tumor-intrinsic mechanisms of immune escape in liver cancer, specifically in the context of HCC.
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http://dx.doi.org/10.3389/fimmu.2021.642958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107356PMC
April 2021

BRAF-induced senescence drives Langerhans cell histiocytosis pathophysiology.

Nat Med 2021 05 6;27(5):851-861. Epub 2021 May 6.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Langerhans cell histiocytosis (LCH) is a potentially fatal condition characterized by granulomatous lesions with characteristic clonal mononuclear phagocytes (MNPs) harboring activating somatic mutations in mitogen-activated protein kinase (MAPK) pathway genes, most notably BRAF. We recently discovered that the BRAF mutation can also affect multipotent hematopoietic progenitor cells (HPCs) in multisystem LCH disease. How the BRAF mutation in HPCs leads to LCH is not known. Here we show that enforced expression of the BRAF mutation in early mouse and human multipotent HPCs induced a senescence program that led to HPC growth arrest, apoptosis resistance and a senescence-associated secretory phenotype (SASP). SASP, in turn, promoted HPC skewing toward the MNP lineage, leading to the accumulation of senescent MNPs in tissue and the formation of LCH lesions. Accordingly, elimination of senescent cells using INK-ATTAC transgenic mice, as well as pharmacologic blockade of SASP, improved LCH disease in mice. These results identify senescent cells as a new target for the treatment of LCH.
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http://dx.doi.org/10.1038/s41591-021-01304-xDOI Listing
May 2021

Manipulating and tracking single hepatocyte behavior during mouse liver regeneration by performing hydrodynamic tail vein injection.

STAR Protoc 2021 Jun 9;2(2):100440. Epub 2021 Apr 9.

Department of Medicine/Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Studies to identify genes relevant to mammalian hepatocyte biology are largely carried out using germline genetic-engineering approaches, which can be costly and time-consuming. We describe hydrodynamic tail vein injection as an alternative approach to introduce genetic elements into hepatocytes. Transfected hepatocytes can then be traced with a GFP reporter enabling the use of immunohistochemistry and FACS sorting to examine the changes in hepatocyte gene expression and proliferation during liver regeneration induced by 2/3 partial hepatectomy (PH). For complete details on the use and execution of this protocol, please refer to Wang et al. (2019).
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http://dx.doi.org/10.1016/j.xpro.2021.100440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055704PMC
June 2021

NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Nature 2021 Apr 24;592(7854):450-456. Epub 2021 Mar 24.

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need. Here we report the progressive accumulation of exhausted, unconventionally activated CD8PD1 T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8PD1 T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8PD1CXCR6, TOX, and TNF T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8 T cells or TNF neutralization, suggesting that CD8 T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8PD1 T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.
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http://dx.doi.org/10.1038/s41586-021-03362-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046670PMC
April 2021

Nrf2 and β-catenin coactivation in hepatocellular cancer: Biological and therapeutic implications.

Hepatology 2021 Feb 2. Epub 2021 Feb 2.

Department of Pathology, University of Pittsburgh, School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA.

Background: Hepatocellular cancer (HCC) remains a major unmet clinical need. Although activating CTNNB1 mutations are seen in prominent subsets of HCC cases, these by themselves are insufficient for hepatocarcinogenesis. Co-expression of mutant CTNNB1 with clinically relevant co-occurrence has yielded HCCs. Here, we identify cooperation between β-catenin and Nrf2 signaling in HCC.

Methods: Public HCC datasets were assessed for concomitant presence of CTNNB1 mutations and either mutations in NFE2L2 or KEAP1, or Nrf2 activation by gene signature. HCC development in mice and similarity to human HCC subsets was assessed following co-expression of T41A-CTNNB1 with either WT-, G31A- or T80K-NFE2L2. Based on mTORC1 activation in CTNNB1-mutated HCCs, response of preclinical HCC to mTOR inhibitor was investigated.

Results: Overall, 9% of HCC cases showed concomitant CTNNB1 mutations and Nrf2 activation, subsets of which were due to mutations in NFE2L2/KEAP1. Co-expression of mutated-CTNNB1 with mutant-NFE2L2 but not WT-NFE2L2 led to HCC development and mortality by 12-14 weeks. These HCCs were positive for β-catenin targets like Glutamine synthetase and Cyclin-D1, and Nrf2 targets like NAD(P)H Quinone Dehydrogenase 1 and peroxiredoxin 1. RNA-seq and pathway analysis showed high concordance of preclinical HCC to human HCC subset showing activation of unique (Iron Homeostasis and Glioblastoma Multiforme signaling) and expected (Glutamine Metabolism) pathways. NFE2L2-CTNNB1 HCC mice were treated with mTOR inhibitor everolimus (5mg/kg diet ad libitum), which led to >50% decrease in tumor burden. Conclusion Co-activation of β-catenin and Nrf2 is evident in 9% of all human HCCs. Co-expression of mutant-NFE2L2 and mutant-CTNNB1 led to clinically relevant HCC development in mice, which responded to mTOR inhibitors. Thus, this model has both biological and therapeutic implications.
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http://dx.doi.org/10.1002/hep.31730DOI Listing
February 2021

Liver metastases inhibit immunotherapy efficacy.

Nat Med 2021 01;27(1):25-27

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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http://dx.doi.org/10.1038/s41591-020-01190-9DOI Listing
January 2021

Turning up our understanding of liver cancer by a notch.

J Hepatol 2021 Mar 17;74(3):502-504. Epub 2020 Dec 17.

Aix Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), UMR7288, Parc Scientifique de Luminy, Marseille, France. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.10.027DOI Listing
March 2021

Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses Against Hepatocellular Carcinoma.

Cancers (Basel) 2020 Nov 16;12(11). Epub 2020 Nov 16.

Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain.

Therapies based on immune checkpoint inhibitors (ICPI) have yielded promising albeit limited results in patients with hepatocellular carcinoma (HCC). Vaccines have been proposed as combination partners to enhance response rates to ICPI. Thus, we analyzed the combined effect of a vaccine based on the TLR4 ligand cold-inducible RNA binding protein (CIRP) plus ICPI. Mice were immunized with vaccines containing ovalbumin linked to CIRP (OVA-CIRP), with or without ICPI, and antigen-specific responses and therapeutic efficacy were tested in subcutaneous and orthotopic mouse models of liver cancer. OVA-CIRP elicited polyepitopic T-cell responses, which were further enhanced when combined with ICPI (anti-PD-1 and anti-CTLA-4). Combination of OVA-CIRP with ICPI enhanced ICPI-induced therapeutic responses when tested in subcutaneous and intrahepatic B16-OVA tumors, as well as in the orthotopic PM299L HCC model. This effect was associated with higher OVA-specific T-cell responses in the periphery, although many tumor-infiltrating lymphocytes still displayed an exhausted phenotype. Finally, a new vaccine containing human glypican-3 linked to CIRP (GPC3-CIRP) induced clear responses in humanized HLA-A2.01 transgenic mice, which increased upon combination with ICPI. Therefore, CIRP-based vaccines may generate anti-tumor immunity to enhance ICPI efficacy in HCC, although blockade of additional checkpoint molecules and immunosuppressive targets should be also considered.
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http://dx.doi.org/10.3390/cancers12113397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696968PMC
November 2020

Cooperation Between Distinct Cancer Driver Genes Underlies Intertumor Heterogeneity in Hepatocellular Carcinoma.

Gastroenterology 2020 12 16;159(6):2203-2220.e14. Epub 2020 Aug 16.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background And Aims: The pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of available therapies. In spite of this, the existing mouse models only recapitulate a small portion of HCC inter-tumor heterogeneity, limiting the understanding of the disease and the nomination of personalized therapies. Here, we aimed at establishing a novel collection of HCC mouse models that captured human HCC diversity.

Methods: By performing hydrodynamic tail-vein injections, we tested the impact of altering a well-established HCC oncogene (either MYC or β-catenin) in combination with an additional alteration in one of eleven other genes frequently mutated in HCC. Of the 23 unique pairs of genetic alterations that we interrogated, 9 were able to induce HCC. The established HCC mouse models were characterized at histopathological, immune, and transcriptomic level to identify the unique features of each model. Murine HCC cell lines were generated from each tumor model, characterized transcriptionally, and used to identify specific therapies that were validated in vivo.

Results: Cooperation between pairs of driver genes produced HCCs with diverse histopathology, immune microenvironments, transcriptomes, and drug responses. Interestingly, MYC expression levels strongly influenced β-catenin activity, indicating that inter-tumor heterogeneity emerges not only from specific combinations of genetic alterations but also from the acquisition of expression-dependent phenotypes.

Conclusions: This novel collection of murine HCC models and corresponding cell lines establishes the role of driver genes in diverse contexts and enables mechanistic and translational studies.
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http://dx.doi.org/10.1053/j.gastro.2020.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726023PMC
December 2020

Mouse Models of Oncoimmunology in Hepatocellular Carcinoma.

Clin Cancer Res 2020 10 23;26(20):5276-5286. Epub 2020 Apr 23.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.

Liver cancer is the fourth leading cause of cancer-related mortality worldwide and incidence is on the rise. Hepatocellular carcinoma (HCC) is the most common form of liver cancer, with a complex etiology and limited treatment options. The standard-of-care treatment for patients with advanced HCC is sorafenib, a tyrosine kinase inhibitor that offers limited survival benefit. In the past years, therapeutic options for the treatment of advanced HCC have increased substantially, including additional multikinase inhibitors as well as immune checkpoint inhibitors. Nivolumab and pembrolizumab were approved in 2017 and 2018, respectively, as second-line treatment in advanced HCC. These drugs, both targeting the programmed death-1 pathway, demonstrate unprecedented results, with objective response rates of approximately 20%. However, the majority of patients do not respond, necessitating the identification of biomarkers of response and resistance to immunotherapy. With the recent success of immunotherapies in oncology, mouse models that better recapitulate the human disease and antitumor immune response are needed. This review lists ongoing clinical trials testing immunotherapy in HCC, briefly discusses the unique immunosuppressive environment of the liver, and then delves into the most applicable current murine model systems to study oncoimmunology within the context of HCC, including syngeneic, genetically engineered, and humanized models.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572462PMC
October 2020

Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation.

Cancer Cell 2020 04 26;37(4):584-598.e11. Epub 2020 Mar 26.

Bioinformatics Core Facility of the Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX 75390, USA.

Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms.
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http://dx.doi.org/10.1016/j.ccell.2020.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292228PMC
April 2020

Novel patient-derived preclinical models of liver cancer.

J Hepatol 2020 02;72(2):239-249

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, USA. Electronic address:

Preclinical models of cancer based on the use of human cancer cell lines and mouse models have enabled discoveries that have been successfully translated into patients. And yet the majority of clinical trials fail, emphasising the urgent need to improve preclinical research to better interrogate the potential efficacy of each therapy and the patient population most likely to benefit. This is particularly important for liver malignancies, which lack highly efficient treatments and account for hundreds of thousands of deaths around the globe. Given the intricate network of genetic and environmental factors that contribute to liver cancer development and progression, the identification of new druggable targets will mainly depend on establishing preclinical models that mirror the complexity of features observed in patients. The development of new 3D cell culture systems, originating from cells/tissues isolated from patients, might create new opportunities for the generation of more specific and personalised therapies. However, these systems are unable to recapitulate the tumour microenvironment and interactions with the immune system, both proven to be critical influences on therapeutic outcomes. Patient-derived xenografts, in particular with humanised mouse models, more faithfully mimic the physiology of human liver cancer but are costly and time-consuming, which can be prohibitive for personalising therapies in the setting of an aggressive malignancy. In this review, we discuss the latest advances in the development of more accurate preclinical models to better understand liver cancer biology and identify paradigm-changing therapies, stressing the importance of a bi-directional communicative flow between clinicians and researchers to establish reliable model systems and determine how best to apply them to expanding our current knowledge.
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http://dx.doi.org/10.1016/j.jhep.2019.09.028DOI Listing
February 2020

Genetic Modification of CD8 T Cells to Express EGFR: Potential Application for Adoptive T Cell Therapies.

Front Immunol 2019 20;10:2990. Epub 2019 Dec 20.

Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.

Adoptive immunotherapy with -expanded tumor-infiltrating lymphocytes (TILs) has achieved objective clinical responses in a significant number of patients with cancer. The failure of many patients to develop long-term tumor control may be, in part, due to exhaustion of transferred T cells in the presence of a hostile tumor microenvironment. In several tumor types, growth and survival of carcinoma cells appear to be sustained by a network of receptors/ligands of the ErbB family. We speculated that if transferred T cells could benefit from EGFR ligands produced by the tumor, they might proliferate better and exert their anti-tumor activities more efficiently. We found that CD8 T cells transduced with a retrovirus to express EGFR responded to EGFR ligands activating the EGFR signaling pathway. These EGFR-expressing effector T cells proliferated better and produced more IFN-γ and TNF-α in the presence of EGFR ligands produced by tumor cells . EGFR-expressing CD8 T cells from OT-1 mice were more efficient killing B16-OVA cells than control OT-1 CD8 T cells. Importantly, EGFR-expressing OT-1 T cells injected into B16-OVA tumor bearing mice were recruited into the tumor, expressed lower levels of the exhaustion markers PD1, TIGIT, and LAG3, and were more efficient in delaying tumor growth. Our results suggest that genetic modification of CD8 T cells to express EGFR might be considered in immunotherapeutic strategies based on adoptive transfer of anti-tumor T cells against cancers expressing EGFR ligands.
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http://dx.doi.org/10.3389/fimmu.2019.02990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934060PMC
November 2020

Epigenetic Compensation Promotes Liver Regeneration.

Dev Cell 2019 07 20;50(1):43-56.e6. Epub 2019 Jun 20.

Department of Medicine/Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Program in Biology, New York University Abu Dhabi, Abu Dhabi, P.O. Box 129188, United Arab Emirates. Electronic address:

Two major functions of the epigenome are to regulate gene expression and to suppress transposons. It is unclear how these functions are balanced during physiological challenges requiring tissue regeneration, where exquisite coordination of gene expression is essential. Transcriptomic analysis of seven time points following partial hepatectomy identified the epigenetic regulator UHRF1, which is essential for DNA methylation, as dynamically expressed during liver regeneration in mice. UHRF1 deletion in hepatocytes (Uhrf1) caused genome-wide DNA hypomethylation but, surprisingly, had no measurable effect on gene or transposon expression or liver homeostasis. Partial hepatectomy of Uhrf1 livers resulted in early and sustained activation of proregenerative genes and enhanced liver regeneration. This was attributed to redistribution of H3K27me3 from promoters to transposons, effectively silencing them and, consequently, alleviating repression of liver regeneration genes, priming them for expression in Uhrf1 livers. Thus, epigenetic compensation safeguards the genome against transposon activation, indirectly affecting gene regulation.
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http://dx.doi.org/10.1016/j.devcel.2019.05.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615735PMC
July 2019

Phenotype-Based Screens with Conformation-Specific Inhibitors Reveal p38 Gamma and Delta as Targets for HCC Polypharmacology.

Mol Cancer Ther 2019 09 18;18(9):1506-1519. Epub 2019 Jun 18.

Department of Oncological Sciences, The Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai, New York, New York.

The approved kinase inhibitors for hepatocellular carcinoma (HCC) are not matched to specific mutations within tumors. This has presented a daunting challenge; without a clear target or mechanism, no straightforward path has existed to guide the development of improved therapies for HCC. Here, we combine phenotypic screens with a class of conformation-specific kinase inhibitors termed type II to identify a multikinase inhibitor, AD80, with antitumoral activity across a variety of HCC preclinical models, including mouse xenografts. Mass spectrometry profiling found a number of kinases as putative targets for AD80, including several receptor and cytoplasmic protein kinases. Among these, we found p38 gamma and delta as direct targets of AD80. Notably, a closely related analog of AD80 lacking p38δ/γ activity, but retaining several other off-target kinases, lost significant activity in several HCC models. Moreover, forced and sustained MKK6 → p38→ATF2 signaling led to a significant reduction of AD80 activity within HCC cell lines. Together with HCC survival data in The Cancer Genome Atlas and RNA-seq analysis, we suggest p38 delta and gamma as therapeutic targets in HCC and an "AD80 inhibition signature" as identifying those patients with best clinical outcomes.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017390PMC
September 2019

β-Catenin Activation Promotes Immune Escape and Resistance to Anti-PD-1 Therapy in Hepatocellular Carcinoma.

Cancer Discov 2019 08 11;9(8):1124-1141. Epub 2019 Jun 11.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.

PD-1 immune checkpoint inhibitors have produced encouraging results in patients with hepatocellular carcinoma (HCC). However, what determines resistance to anti-PD-1 therapies is unclear. We created a novel genetically engineered mouse model of HCC that enables interrogation of how different genetic alterations affect immune surveillance and response to immunotherapies. Expression of exogenous antigens in HCCs led to T cell-mediated immune surveillance, which was accompanied by decreased tumor formation and increased survival. Some antigen-expressing HCCs escaped the immune system by upregulating the β-catenin (CTNNB1) pathway. Accordingly, expression of exogenous antigens in HCCs had no effect, demonstrating that β-catenin promoted immune escape, which involved defective recruitment of dendritic cells and consequently impaired T-cell activity. Expression of chemokine CCL5 in antigen-expressing HCCs restored immune surveillance. Finally, β-catenin-driven tumors were resistant to anti-PD-1. In summary, β-catenin activation promotes immune escape and resistance to anti-PD-1 and could represent a novel biomarker for HCC patient exclusion. SIGNIFICANCE: Determinants of response to anti-PD-1 immunotherapies in HCC are poorly understood. Using a novel mouse model of HCC, we show that β-catenin activation promotes immune evasion and resistance to anti-PD-1 therapy and could potentially represent a novel biomarker for HCC patient exclusion...
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http://dx.doi.org/10.1158/2159-8290.CD-19-0074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677618PMC
August 2019

Hepatocellular carcinoma: killing one bird with two stones.

Gut 2019 09 10;68(9):1543-1544. Epub 2019 May 10.

Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.

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http://dx.doi.org/10.1136/gutjnl-2019-318649DOI Listing
September 2019

Iron overload and liver cancer.

J Exp Med 2019 04 18;216(4):723-724. Epub 2019 Mar 18.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY

In this issue of , Muto et al. (https://doi.org/10.1084/jem.20180900) generate a novel mouse model of liver cancer induced by iron overload by deleting the iron-sensing ubiquitin ligase FBXL5 specifically in hepatocytes and exposure to a chemical carcinogen.
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http://dx.doi.org/10.1084/jem.20190257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446872PMC
April 2019

Functional screening to identify senescence regulators in cancer.

Curr Opin Genet Dev 2019 02 14;54:17-24. Epub 2019 Mar 14.

Hopp Children's Cancer Center (KiTZ) and Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Cellular senescence is implicated in numerous biological processes, and can play pleiotropic, sometimes opposing, roles in cancer. Several triggers, cell types, contexts, and senescence-associated phenotypes introduce a multitude of possibilities when studying this process and its biological consequences. Recent studies continue to characterize cellular senescence at different levels, using a combination of functional screens, in silico analysis, omics characterizations and more targeted studies. However, a comprehensive analysis of its context-dependent effects and multiple phenotypes is required. Application of state-of-the-art and emerging technologies will increase our understanding of this complex process and better guide future strategies to harness senescence to our advantage, or to target it when detrimental.
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http://dx.doi.org/10.1016/j.gde.2019.02.001DOI Listing
February 2019

Nuclear Pores Promote Lethal Prostate Cancer by Increasing POM121-Driven E2F1, MYC, and AR Nuclear Import.

Cell 2018 08 9;174(5):1200-1215.e20. Epub 2018 Aug 9.

Cancer Biology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; Medical Oncology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; Pathology Department, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

Nuclear pore complexes (NPCs) regulate nuclear-cytoplasmic transport, transcription, and genome integrity in eukaryotic cells. However, their functional roles in cancer remain poorly understood. We interrogated the evolutionary transcriptomic landscape of NPC components, nucleoporins (Nups), from primary to advanced metastatic human prostate cancer (PC). Focused loss-of-function genetic screen of top-upregulated Nups in aggressive PC models identified POM121 as a key contributor to PC aggressiveness. Mechanistically, POM121 promoted PC progression by enhancing importin-dependent nuclear transport of key oncogenic (E2F1, MYC) and PC-specific (AR-GATA2) transcription factors, uncovering a pharmacologically targetable axis that, when inhibited, decreased tumor growth, restored standard therapy efficacy, and improved survival in patient-derived pre-clinical models. Our studies molecularly establish a role of NPCs in PC progression and give a rationale for NPC-regulated nuclear import targeting as a therapeutic strategy for lethal PC. These findings may have implications for understanding how NPC deregulation contributes to the pathogenesis of other tumor types.
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http://dx.doi.org/10.1016/j.cell.2018.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150493PMC
August 2018

Erratum: DNA sensing in senescence.

Nat Cell Biol 2017 11;19(12):1441

This corrects the article DOI: 10.1038/ncb3603.
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http://dx.doi.org/10.1038/ncb3644DOI Listing
November 2017

Cell type-specific pharmacological kinase inhibition for cancer chemoprevention.

Nanomedicine 2018 02 20;14(2):317-325. Epub 2017 Nov 20.

Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Safety is prerequisite for preventive medicine, but non-toxic agents are generally ineffective as clinical chemoprevention. Here we propose a strategy overcoming this challenge by delivering molecular-targeted agent specifically to the effector cell type to achieve sufficient potency, while circumventing toxicity in the context of cancer chemoprevention. Hepatic myofibroblasts drive progressive fibrosis that results in cirrhosis and liver cancer. In a rat model of cirrhosis-driven liver cancer, a small molecule epidermal growth factor receptor inhibitor, erlotinib, was delivered specifically to myofibroblasts by a versatile nanoparticle-based system, targeting platelet-derived growth factor receptor-beta uniquely expressed on their surface in the liver. With systemic administration of erlotinib, tumor burden was reduced to 31%, which was further improved to 21% by myofibroblast-targeted delivery even with reduced erlotinib dose (7.3-fold reduction with equivalent erlotinib dose) and less hepatocyte damage. These findings demonstrate a strategy, cell type-specific kinase inhibition, for more effective and safer precision cancer chemoprevention.
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http://dx.doi.org/10.1016/j.nano.2017.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844817PMC
February 2018

DNA sensing in senescence.

Nat Cell Biol 2017 08;19(9):1008-1009

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York 10029, USA and at the Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA.

Cellular senescence, a cell-autonomous growth arrest program, also executes pleiotropic non-cell-autonomous activities through the senescence-associated secretory phenotype (SASP). The innate cGAS-STING DNA-sensing pathway is now shown to regulate senescence by recognizing cytosolic DNA and inducing SASP factors, uncovering an unexpected link between these two previously unrelated pathways.
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http://dx.doi.org/10.1038/ncb3603DOI Listing
August 2017

Therapeutic editing of hepatocyte genome in vivo.

J Hepatol 2017 10 17;67(4):818-828. Epub 2017 May 17.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, USA. Electronic address:

The recent development of gene editing platforms enables making precise changes in the genome of eukaryotic cells. Programmable nucleases, such as meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeat (CRISPR)-associated nucleases have revolutionized the way research is conducted as they facilitate the rapid production of mutant or knockout cellular and animal models. These same genetic tools can potentially be applied to cure or alleviate a variety of diseases, including genetic diseases that lack an efficient therapy. Thus, gene editing platforms could be used for correcting mutations that cause a disease, restoration of the expression of genes that are missing, or be used for the removal of deleterious genes or viral genomes. In the context of liver diseases, genome editing could be developed to treat not only hereditary monogenic liver diseases but also hepatitis B infection and diseases that have both genetic and non-genetic components. While the prospect of translating these therapeutic strategies to a clinical setting is highly appealing, there are numerous challenges that need to be addressed first. Safety, efficiency, specificity, and delivery are some of the obstacles that will need to be addressed before each specific gene treatment is safely used in patients. Here, we discuss the most used gene editing platforms, their mechanisms of action, their potential for liver disease treatment, the most pressing challenges, and future prospects.
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http://dx.doi.org/10.1016/j.jhep.2017.05.012DOI Listing
October 2017

Strategies for HCC target discovery.

Aging (Albany NY) 2017 Apr;9(4):1088-1089

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

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http://dx.doi.org/10.18632/aging.101233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425115PMC
April 2017

Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway.

Cell Rep 2017 03;18(10):2480-2493

Epigenetics & Cellular Senescence Group, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK. Electronic address:

Cellular senescence is an important in vivo mechanism that prevents the propagation of damaged cells. However, the precise mechanisms regulating senescence are not well characterized. Here, we find that ITGB3 (integrin beta 3 or β3) is regulated by the Polycomb protein CBX7. β3 expression accelerates the onset of senescence in human primary fibroblasts by activating the transforming growth factor β (TGF-β) pathway in a cell-autonomous and non-cell-autonomous manner. β3 levels are dynamically increased during oncogene-induced senescence (OIS) through CBX7 Polycomb regulation, and downregulation of β3 levels overrides OIS and therapy-induced senescence (TIS), independently of its ligand-binding activity. Moreover, cilengitide, an αvβ3 antagonist, has the ability to block the senescence-associated secretory phenotype (SASP) without affecting proliferation. Finally, we show an increase in β3 levels in a subset of tissues during aging. Altogether, our data show that integrin β3 subunit is a marker and regulator of senescence.
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http://dx.doi.org/10.1016/j.celrep.2017.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357738PMC
March 2017