ABSTRACT
PURPOSE OF REVIEW: To summarize and evaluate the literature on treatment approaches for oligometastatic and locally recurrent urothelial cancer. RECENT FINDINGS: There is no clear definition for oligometastatic urothelial cancers due to limited data. Studies focusing on oligometastatic and locally recurrent urothelial cancer have been primarily retrospective. Treatment options include local therapy with surgery or radiation, and generalized systemic therapy such as chemotherapy or immunotherapy. Oligometastatic and locally recurrent urothelial cancers remain challenging to manage, and treatment requires an interdisciplinary approach. Systemic therapy is nearly always a component of current care in the form of chemotherapy, but the role of immunotherapy has not been explored. Consideration of surgical and radiation options may improve outcomes, and no studies have compared directly between the two localized treatment options. The development of new prognostic and predictive biomarkers may also enhance the treatment landscape in the future.
Subject(s)
Neoplasm Recurrence, Local , Urinary Bladder Neoplasms , Humans , Neoplasm Recurrence, Local/therapy , Neoplasm Recurrence, Local/pathology , Urinary Bladder Neoplasms/therapy , Urinary Bladder Neoplasms/pathology , Carcinoma, Transitional Cell/therapy , Carcinoma, Transitional Cell/pathology , Carcinoma, Transitional Cell/secondary , Neoplasm Metastasis , Immunotherapy , Combined Modality Therapy , Urologic Neoplasms/pathology , Urologic Neoplasms/therapy , PrognosisABSTRACT
We identified and validated a collection of circular RNAs (circRNAs) in Drosophila melanogaster. We show that depletion of the pro-viral circRNA circATP8B(2), but not its linear siblings, compromises viral infection both in cultured Drosophila cells and in vivo. In addition, circATP8B(2) is enriched in the fly gut, and gut-specific depletion of circATP8B(2) attenuates viral replication in an oral infection model. Furthermore, circATP8B(2) depletion results in increased levels of reactive oxygen species (ROS) and enhanced expression of dual oxidase (Duox), which produces ROS. Genetic and pharmacological manipulations of circATP8B(2)-depleted flies that reduce ROS levels rescue the viral replication defects elicited by circATP8B(2) depletion. Mechanistically, circATP8B(2) associates with Duox, and circATP8B(2)-Duox interaction is crucial for circATP8B(2)-mediated modulation of Duox activity. In addition, Gαq, a G protein subunit required for optimal Duox activity, acts downstream of circATP8B(2). We conclude that circATP8B(2) regulates antiviral defense by modulating Duox expression and Duox-dependent ROS production.
Subject(s)
Drosophila Proteins , Drosophila melanogaster , RNA, Circular , Reactive Oxygen Species , Animals , Reactive Oxygen Species/metabolism , RNA, Circular/genetics , RNA, Circular/metabolism , Drosophila melanogaster/immunology , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Drosophila Proteins/metabolism , Drosophila Proteins/genetics , Virus Replication , RNA/metabolism , RNA/genetics , NADPH Oxidases/metabolism , NADPH Oxidases/genetics , Dual Oxidases/metabolism , Dual Oxidases/geneticsABSTRACT
Despite recent advances in molecular therapeutics, lung cancer is still a leading cause of cancer deaths. Currently, limited targeted therapy options and acquired drug resistance present significant barriers in the treatment of patients with lung cancer. New strategies in drug development, including those that take advantage of the intracellular ubiquitin-proteasome system to induce targeted protein degradation, have the potential to advance the field of personalized medicine for patients with lung cancer. Specifically, small molecule proteolysis targeting chimeras (PROTACs), consisting of two ligands connected by a linker that bind to a target protein and an E3 ubiquitin ligase, have been developed against many cancer targets, providing promising opportunities for advanced lung cancer. In this review, we focus on the rationale for PROTAC therapy as a new targeted therapy and the current status of PROTAC development in lung cancer.
Subject(s)
Lung Neoplasms , Proteasome Endopeptidase Complex , Humans , Proteasome Endopeptidase Complex/metabolism , Proteins/metabolism , Proteolysis , Ubiquitin-Protein Ligases/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/geneticsABSTRACT
Epithelial-mesenchymal transition (EMT) is implicated in tumor metastasis and therapeutic resistance. It remains a challenge to target cancer cells that have undergone EMT. The Snail family of key EMT-inducing transcription factors directly binds to and transcriptionally represses not only epithelial genes but also a myriad of additional genomic targets that may carry out significant biological functions. Therefore, we reasoned that EMT inherently causes various concomitant phenotypes, some of which may create targetable vulnerabilities for cancer treatment. In the present study, we found that Snail transcription factors bind to the promoters of multiple genes encoding subunits of the AMP-activated protein kinase (AMPK) complex, and expression of AMPK genes was markedly downregulated by EMT. Accordingly, high AMPK expression in tumors correlated with epithelial cell markers and low AMPK expression in tumors was strongly associated with adverse prognosis. AMPK is the principal sensor of cellular energy status. In response to energy stress, AMPK is activated and critically reprograms cellular metabolism to restore energy homeostasis and maintain cell survival. We showed that activation of AMPK by energy stress was severely impaired by EMT. Consequently, EMT cancer cells became hypersensitive to a variety of energy stress conditions and primarily underwent pyroptosis, a regulated form of necrotic cell death. Collectively, the study suggests that EMT impedes the activation of AMPK signaling induced by energy stress and sensitizes cancer cells to pyroptotic cell death under energy stress conditions. Therefore, while EMT promotes malignant progression, it concurrently induces collateral vulnerabilities that may be therapeutically exploited.
Subject(s)
Epithelial-Mesenchymal Transition , Neoplasms , Pyroptosis , AMP-Activated Protein Kinases/metabolism , Epithelial-Mesenchymal Transition/genetics , Humans , Neoplasms/genetics , Neoplasms/metabolism , Snail Family Transcription Factors , Stress, PhysiologicalABSTRACT
Lung cancer with loss-of-function of the LKB1 tumor suppressor is a common aggressive subgroup with no effective therapies. LKB1-deficiency induces constitutive activation of cAMP/CREB-mediated transcription by a family of three CREB-regulated transcription coactivators (CRTC1-3). However, the significance and mechanism of CRTC activation in promoting the aggressive phenotype of LKB1-null cancer remain poorly characterized. Here, we observed overlapping CRTC expression patterns and mild growth phenotypes of individual CRTC-knockouts in lung cancer, suggesting functional redundancy of CRTC1-3. We consequently designed a dominant-negative mutant (dnCRTC) to block all three CRTCs to bind and co-activate CREB. Expression of dnCRTC efficiently inhibited the aberrantly activated cAMP/CREB-mediated oncogenic transcriptional program induced by LKB1-deficiency, and specifically blocked the growth of human and murine LKB1-inactivated lung cancer. Collectively, this study provides direct proof for an essential role of the CRTC-CREB activation in promoting the malignant phenotypes of LKB1-null lung cancer and proposes the CRTC-CREB interaction interface as a novel therapeutic target.
Subject(s)
Cyclic AMP Response Element-Binding Protein/genetics , Lung Neoplasms , Protein Serine-Threonine Kinases/genetics , Transcription Factors/genetics , A549 Cells , AMP-Activated Protein Kinase Kinases , AMP-Activated Protein Kinases , Animals , CRISPR-Cas Systems , Cell Line, Tumor , Cyclic AMP Response Element-Binding Protein/metabolism , Gene Editing , Heterografts , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Protein Serine-Threonine Kinases/metabolism , Transcription Factors/metabolism , Transcriptome/geneticsABSTRACT
No effective systemic treatment is available for patients with unresectable, recurrent, or metastatic mucoepidermoid carcinoma (MEC), the most common salivary gland malignancy. MEC is frequently associated with a t(11;19)(q14-21;p12-13) translocation that creates a CRTC1-MAML2 fusion gene. The CRTC1-MAML2 fusion exhibited transforming activity in vitro; however, whether it serves as an oncogenic driver for MEC establishment and maintenance in vivo remains unknown. Here, we show that doxycycline-induced CRTC1-MAML2 knockdown blocked the growth of established MEC xenografts, validating CRTC1-MAML2 as a therapeutic target. We further generated a conditional transgenic mouse model and observed that Cre-induced CRTC1-MAML2 expression caused 100% penetrant formation of salivary gland tumors resembling histological and molecular characteristics of human MEC. Molecular analysis of MEC tumors revealed altered p16-CDK4/6-RB pathway activity as a potential cooperating event in promoting CRTC1-MAML2-induced tumorigenesis. Cotargeting of aberrant p16-CDK4/6-RB signaling and CRTC1-MAML2 fusion-activated AREG/EGFR signaling with the respective CDK4/6 inhibitor Palbociclib and EGFR inhibitor Erlotinib produced enhanced antitumor responses in vitro and in vivo. Collectively, this study provides direct evidence for CRTC1-MAML2 as a key driver for MEC development and maintenance and identifies a potentially novel combination therapy with FDA-approved EGFR and CDK4/6 inhibitors as a potential viable strategy for patients with MEC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Mucoepidermoid/genetics , Salivary Gland Neoplasms/genetics , Trans-Activators/genetics , Transcription Factors/genetics , Animals , Carcinoma, Mucoepidermoid/drug therapy , Carcinoma, Mucoepidermoid/pathology , Cell Line, Tumor , Cyclin-Dependent Kinase 4/genetics , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Doxycycline/pharmacology , ErbB Receptors/genetics , ErbB Receptors/metabolism , Gene Expression Regulation, Neoplastic , Humans , Mice, Transgenic , Neoplasms, Experimental/genetics , Neoplasms, Experimental/pathology , Oncogene Fusion , Oncogene Proteins, Fusion/genetics , Retinoblastoma Protein/genetics , Retinoblastoma Protein/metabolism , Salivary Gland Neoplasms/drug therapy , Salivary Gland Neoplasms/pathology , Xenograft Model Antitumor AssaysABSTRACT
We introduce a microfluidic platform that enables off-chip single-cell RNA-seq after multi-generational lineage tracking under controlled culture conditions. We use this platform to generate whole-transcriptome profiles of primary, activated murine CD8+ T-cell and lymphocytic leukemia cell line lineages. Here we report that both cell types have greater intra- than inter-lineage transcriptional similarity. For CD8+ T-cells, genes with functional annotation relating to lymphocyte differentiation and function--including Granzyme B--are enriched among the genes that demonstrate greater intra-lineage expression level similarity. Analysis of gene expression covariance with matched measurements of time since division reveals cell type-specific transcriptional signatures that correspond with cell cycle progression. We believe that the ability to directly measure the effects of lineage and cell cycle-dependent transcriptional profiles of single cells will be broadly useful to fields where heterogeneous populations of cells display distinct clonal trajectories, including immunology, cancer, and developmental biology.