Targeted DNA and RNA Sequencing of Paired Urothelial and Squamous Bladder Cancers Reveals Discordant Genomic and Transcriptomic Events and Unique Therapeutic Implications

Hovelson, Daniel H.; Udager, Aaron M.; McDaniel, Andrew S.; Grivas, Petros; Palmbos, Phillip L.; Tamura, Shuzo; Vega, Lorena Lazo de la; Palapattu, Ganesh S.; Veeneman, Brendan; El-Sawy, Layla; Sadis, Seth; Morgan, Todd M.; Montgomery, Jeffrey S.; Weizer, Alon Z.; Day, Kathleen C.; Neamati, Nouri; Liebert, Monica; Keller, Evan T.; Day, Mark L.; Mehra, Rohit; Tomlins, Scott A.

doi:10.1016/j.eururo.2018.06.047

Cited by 59 publications

(48 citation statements)

References 37 publications

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“…37,38 Furthermore, urothelial and squamous components within the same bladder tumor, which were histologically different from each other, might share the identical genomic alterations, but distinct transcriptional profiles, implicating plasticity of cancer cells in a microenvironment-dependent manner. 39 These data suggest caution in using molecular subtyping based on limited sampling to guide patients with MIBC to drug treatment.…”

Section: Predictive Biomarkers For Cddp-based Chemotherapy In Advancementioning

confidence: 99%

Predictive biomarkers for drug response in bladder cancer

Yoshida¹,

Kates

Fujita

et al. 2019

Int J of Urology

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Bladder cancer is a heterogeneous disease. Interpatient heterogeneity in response to a drug limits treatment options and impairs improvement of patient survival. For example, approximately half of patients do not respond to cisplatin‐based combination chemotherapy, although it is the standard of care for muscle‐invasive and metastatic bladder cancer. The development of robust predictive biomarkers is expected to improve outcomes by enabling clinicians to use chemotherapy only in the patients who will benefit from it. Recent advances in the molecular characterization of bladder cancer showed that the basal subtype of bladder cancer and tumors with inactivating mutations in DNA damage repair genes were associated with greater benefit from cisplatin‐based chemotherapy. The present review summarizes current efforts to develop predictive biomarkers for drug response in bladder cancer, focusing on those that predict the response to cisplatin‐based chemotherapy for advanced bladder cancer. We also review the current situation with regard to the identification of predictive biomarkers for response to intravesical therapy, immune checkpoint inhibitors and molecularly‐targeted drugs. We also discuss the future applications of new technologies, including liquid biopsies and patient‐derived organoids that will also serve as resources for the identification of biomarkers in bladder cancer.

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Section: Predictive Biomarkers For Cddp-based Chemotherapy In Advancementioning

confidence: 99%

Predictive biomarkers for drug response in bladder cancer

Yoshida¹,

Kates

Fujita

et al. 2019

Int J of Urology

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“…Although the presence of morphologic heterogeneity in BC and its relation to clinical outcomes has been recognized for decades, a series of recent studies definitively demonstrate the existence of intratumoral molecular heterogeneity in this common malignancy (3,5), as well as the potentially plastic nature of this heterogeneity. In keeping with specific tenants of the master regulator hypothesis (21), our in vivo and in vitro experimental studies (7,11,18,20,28), as well as additional foundational studies from other groups (6,9,10,22,(29)(30)(31)(32)(33)(34)(35)(36)(37) have identified a series of TFs apparently responsible for maintaining urothelial cell fate and establishing a luminal gene expression pattern in malignant disease.…”

Section: Discussionmentioning

confidence: 99%

“…If advanced BC with intratumoral heterogeneity is largely clonal in nature, the fact that the vast majority of carcinoma in situ (considered the precursor for the majority of advanced BC) lesions are luminal (4) strongly suggests molecular subtype is "plastic" and can evolve over time. This perspective is substantiated by the fact that areas of variant morphology exhibit significant differences in gene expression subtype within a single tumor, yet harbor a large number of identical genetic alterations (5).…”

Section: Introductionmentioning

confidence: 99%

Repression of Transcription Factor AP-2 Alpha by Peroxisome Proliferator Activated Receptor Gamma Reveals a Novel Transcriptional Circuit in basal-squamous Bladder Cancer

Yamashita

Kawasawa

Shuman

et al. 2018

Preprint

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The discovery of bladder cancer transcriptional subtypes provides an opportunity to identify high risk patients, and tailor disease management. Recent studies suggest tumor heterogeneity contributes to "plasticity" of molecular subtype during progression and following treatment. Nonetheless, the transcriptional drivers of the aggressive basal-squamous subtype remain unidentified. As PPARɣ has been repeatedly implicated in the luminal subtype of bladder cancer, we hypothesized inactivation of this transcriptional master regulator during progression results in increased expression of basalsquamous specific transcription factors (TFs) which act to drive aggressive behavior. We initiated a pharmacologic and RNA-seq-based screen to identify PPARɣ-repressed, basal-squamous specific TFs. Hierarchical clustering of RNA-seq data following treatment of a panel of human bladder cancer cell lines with a PPARɣ agonist identified a number of TFs regulated by PPARɣ activation, several of which are implicated in urothelial and squamous differentiation. One PPARɣ-repressed TF implicated in squamous differentiation identified is Transcription Factor Activating Protein 2 alpha (TFAP2A). We show TFAP2A and its paralog TFAP2C are overexpressed in basal-squamous bladder cancer and in squamous areas of cystectomy samples, and that overexpression is associated with increased lymph node metastasis and distant recurrence, respectively. Biochemical analysis confirmed the ability of PPARɣ activation to repress TFAP2A, while PPARɣ antagonist studies indicate the requirement of a functional receptor. In vivo tissue recombination studies show TFAP2A and TFAP2C promote tumor growth in line with the aggressive nature of basal-squamous bladder cancer. Our findings suggest PPARɣ inactivation, as well as TFAP2A and TFAP2C overexpression cooperate with other TFs to promote the basal-squamous transition.

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“…For example, the original identification of a subset of bladder cancers that exhibit an expression pattern similar to basal urothelial cells (i.e., high molecular weight cytokeratins) revealed these tumors are often (but not always) enriched for squamous differentiation [17]. Indeed, recent studies have confirmed connections between the basal gene expression pattern and squamous differentiation in the setting of intratumoral heterogeneity as well [18]. Another example regarding connections between morphologic variation and specific genetic alterations is provided by studies of the aggressive plasmacytoid morphologic variant of bladder cancer.…”

Section: Connections Between Morphologic and Molecular Heterogeneity mentioning

confidence: 99%

Modeling Tumor Heterogeneity in Bladder Cancer: The Current State of the Field and Future Needs

Seyer

Lehman

DeGraff

2019

BLC

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BACKGROUND: Tumor heterogeneity has been recognized in many cancer types for decades. However, the significance of tumor heterogeneity on disease course and clinical outcome in bladder cancer is of more recent interest to researchers and clinicians. This is especially true as morphologic and molecular heterogeneity has the potential to confound accurate diagnosis, efficient prognostication, and subsequent clinical management. While this is true, it is not always clear what laboratory models are available or suitable for the study of these important clinical phenomena. OBJECTIVE: To review in vitro and in vivo laboratory models for the study of morphologic and molecular tumor heterogeneity in bladder cancer. METHODS: We undertook a review of PubMed with a focus on identifying suitable models for the study of tumor heterogeneity in bladder cancer. RESULTS: We provide a review of common in vivo (genetically engineered mice and patient-derived xenografts) and in vitro (established cell lines and organoid systems) models and discuss their utility in the study of morphologic and molecular tumor heterogeneity in bladder cancer. CONCLUSION: Genetically engineered mouse models and patient-derived xenografts provide complementary approaches for the study of tumor heterogeneity in bladder cancer. In addition, cell culture-based systems provide a system amenable to genetic manipulation and mechanistic studies, while organoid systems bridge the gap between in vivo and in vitro systems. However, the availability of models to study molecular heterogeneity is limited, partly because of a relative lack of molecular characterization of available models. In summary, while models for the study of specific subsets of morphologic heterogeneity are available, more models are required for studies of molecular heterogeneity. This shortcoming could be partially addressed by more comprehensively characterizing currently available model systems. In addition, each system/approach has advantages and disadvantages, and care should be taken when selecting a given model.

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Targeted DNA and RNA Sequencing of Paired Urothelial and Squamous Bladder Cancers Reveals Discordant Genomic and Transcriptomic Events and Unique Therapeutic Implications

Cited by 59 publications

References 37 publications

Predictive biomarkers for drug response in bladder cancer

Predictive biomarkers for drug response in bladder cancer

Repression of Transcription Factor AP-2 Alpha by Peroxisome Proliferator Activated Receptor Gamma Reveals a Novel Transcriptional Circuit in basal-squamous Bladder Cancer

Modeling Tumor Heterogeneity in Bladder Cancer: The Current State of the Field and Future Needs

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