TMIC-26. PRECLINICAL MODEL SYSTEMS OF GLIOBLASTOMA REVEAL MICROENVIRONMENTAL PROGRAMS AND DEPENDENCIES IN PATIENT TUMORS

Abstract Patient-derived model systems serve as a platform for translational research representing the heterogeneity of human cancers, and their success in recapitulating disease-driving genomic alterations is well-documented. While recent studies have demonstrated genomic and functional divergence in patient-derived models with passaging, the need for accurate preclinical models remains. Glioblastoma (GBM) is the most common and aggressive primary brain tumor, and thus far preclinical models have failed to consistently replicate the responses found in patients. We therefore aimed to evaluate the multi-omic fidelity of low-passage GBM model systems across in vitro and in vivo environments and to elucidate the molecular features in which they differ. To this end we established a biobank of glioma direct-from-patient orthotopic xenograft (GliomaPDOX) models and primary gliomasphere cultures (GSCs) and performed whole-exome and RNA sequencing of over 40 purified patient tumors and their matched GliomaPDOXs and GSCs to facilitate paired comparisons across a gradient of full tumor microenvironment (TME) presence. We observed global genomic and transcriptomic fidelity in both systems, but specific programmatic gene expression differences associated with cell-cell interactions in the brain TME, glial cell identity, and in vitro GSC-forming ability. GSCs and GSC-forming ability are strongly associated with an astrocytic gene expression signature, while more stem-like and oligodendrocytic patient tumors including IDH- and H3F3A-mutant GBMs more successfully engraft in GliomaPDOXs. This result implicates the brain TME as a support system for these more stem/oligo-like tumors. Transcription factor network analysis identified regulators of the NOTCH and MYC pathways as strongly enriched in this subgroup of patient tumors and their derivative xenografts, and provides potential targets for therapeutic intervention in near future experiments. Collectively, these findings underline the critical role of the TME in defining GBM cell state, reveal the heterogeneity of TME dependence across patient tumors, and link this dependency to therapeutically actionable molecular features.

Download Full-text

TAMI-48. ENGRAFTMENT PHENOTYPES IN PRECLINICAL MODEL SYSTEMS REVEAL A FUNCTIONAL SUBGROUP OF PATIENT TUMORS DEPENDENT ON THE BRAIN TUMOR MICROENVIRONMENT FOR GROWTH

Neuro-Oncology ◽

10.1093/neuonc/noaa215.935 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii223-ii223

Author(s):

Nicholas Bayley ◽

Christopher Tse ◽

Henan Zhu ◽

Weihong Yan ◽

Laura Gosa ◽

...

Keyword(s):

Brain Tumor ◽

Tumor Microenvironment ◽

Gene Expression Signature ◽

Therapy Response ◽

Model Systems ◽

Preclinical Model ◽

Expression Signature ◽

The Brain

Abstract The derivation of model systems from patient tumors is a requisite for reproducible and high throughput translational cancer research. However, not all tumors can form a model and those that do often fail to capture the molecular diversity specific to their cancer. The potential tumor-intrinsic underpinnings remain largely unknown. In gliomas, the brain tumor microenvironment (TME) is increasingly acknowledged as a regulator of tumor proliferation, invasion, and therapy response. The dissimilar environment of in vitro and heterotopic xenograft models could potentially play a role in the limited fidelity of these model systems. Here we established a culture-free workflow and biobank of 144 glioma direct-from-patient orthotopic xenografts (DPDOX) and 51 parallel gliomasphere cultures (GS). Our direct-from-patient workflow enabled the exclusive in vivo establishment of several gliomas – hereafter termed TME-dependent tumors – including low and high grade mtIDH gliomas and histone H3.3 G34 glioblastomas notoriously difficult to culture in vitro. Through molecular profiling of over 75 patient tumors and their matched derivative models, we find that DPDOX tumors preserve a gene expression signature of neural and glial interactions not found in GS and enriched in brain TME-dependent patient tumors. While these patient tumors span a diversity of clinical diagnoses, network-based inferred transcription factor activity suggests that they converge on shared master regulators of self-renewal driving proneural and OPC/NPC-like cellular state enrichment. Integrating multi-omic profiling from TCGA and other publicly available datasets reveals that this expression signature corresponds to a shared DNA methylation signature across disparate epigenetic subgroups. These findings suggest a brain TME dependence in patient tumors across multiple molecular and clinical classifications of glioma which leads to a lack of representation in model systems failing to recapitulate tumor-promoting components of the TME. Further this work provides a resource to guide translational investigations accounting for influences of the model environment.

Download Full-text

Identification of a Unique Autophagy Gene Expression Signature in CD34+ CML Stem/Progenitor Cells That Correlates with Clinical Response to Imatinib Mesylate

Blood ◽

10.1182/blood.v120.21.1662.1662 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1662-1662

Author(s):

Katharina Rothe ◽

Kevin B.L. Lin ◽

Hanyang Lin ◽

Amy Leung ◽

Donna L. Forrest ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Progenitor Cells ◽

Critical Role ◽

Family Members ◽

Gene Expression Signature ◽

Beclin 1 ◽

Transcript Levels ◽

Autophagy Gene

Abstract Abstract 1662 Chronic myeloid leukemia (CML) stem cells are biologically insensitive to ABL tyrosine kinase inhibitor (TKI) monotherapy and are genetically unstable and rapidly generate imatinib (IM)-resistant mutants in vivo and in vitro. Therefore, there is clearly a need to develop new diagnostic and therapeutic strategies to identify biomarkers to predict patients' response to TKI therapy, and to develop potential therapeutics to target CML stem cells to prevent acquisition of resistance. It has been reported that the induction of macroautophagy (autophagy) may play a critical role in the persistence of primitive CML cells, but how this process is regulated is largely unknown. To investigate whether CML stem/progenitor cells harbor a unique autophagy gene expression profile that could be predictive of patient response to TKI therapy, we have now examined transcript levels of several key autophagy and autophagy-related genes (ATG4A, ATG4B, ATG4C, ATG4D, ATG5, ATG7, ATG12, BECLIN-1, and LC3B) in CD34+ subpopulations obtained at diagnosis from chronic phase (CP) CML patients who were retrospectively classified, after initiation of IM therapy, as IM-responders (n=14) and IM-nonresponders (n=14), as well as normal healthy donors (n=8). Q-RT-PCR analysis revealed that CD34+ CML cells display significantly higher expression levels of ATG4A, ATG4B, ATG4C, and BECLIN-1(p<0.05) compared to normal bone marrow (NBM) cells. Increased transcript levels of ATG4 family members were further observed in CD34+ CML cells upon TKI treatment (IM, dasatinib and nilotinib) in serum-free culture conditions in vitro. Most interestingly, transcript levels of ATG4B were significantly higher in CD34+ CML cells isolated from IM-nonresponders as compared to the same cells from IM-responders (p=0.011), whereas ATG5 was significantly lower in CD34+ CML cells from IM-nonresponders than IM-responders (p=0.003). Moreover, we observed that the stem cell-enriched CD34+CD38− subpopulation from IM-nonresponders expressed higher levels of several ATG genes, including ATG4 family members, than the same cells from IM-responders. In addition, increased transcript levels of ATG4 family members were also observed in peripheral blood (PB) samples of accelerated phase (AP) CML patients (n=7) compared to PB samples from normal individuals (n=4), but there were no significant differences between samples from CP (n=7) vs. AP (n=7). Importantly, our studies show that expression changes in ATG4B and ATG4D in CD34+ CML cells vs. NBM cells correlated with the transcript levels of miR-34a and miR-152, which are predicted to target the ATG4 family. MicroRNA sequence profiling also confirmed that these miRNAs are differentially expressed in CD34+ cells from IM-nonresponders. To further investigate the biological importance of ATG4B, a key cysteine protease involved in the regulation of the autophagy process, IM-sensitive and IM-resistant K562 cells were transduced with an inducible ATG4B shRNA lentiviral vector and knockdown of ATG4B protein expression (∼80%) was confirmed in these cells. Interestingly, the knockdown of ATG4B decreased the viability of these cells (as compared to the scramble control), reduced their proliferative capacity and inhibited the formation of colonies in a colony-forming cell (CFC) assay in the presence or absence of IM. In particular, a reduction in both CFC numbers and colony size were observed in IM-resistant cells with suppression of ATG4B in response to IM treatment, suggesting that ATG4B plays a critical role in IM-induced autophagy. This is the first report investigating potential differences in autophagy gene transcript levels in CD34+ subpopulations from IM-responders vs. IM-nonresponders. The unique gene expression signature identified, particularly differentially expressed ATG4B and ATG5 in IM-nonresponders vs. IM-responders, may serve as a novel, clinically useful biomarker for predicting future TKI therapy response and ATG4B may be a new drug target for directing treatment at CML stem cells. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01163-0 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Qingxia Wei ◽

Olivia Singh ◽

Can Ekinci ◽

Jaspreet Gill ◽

Mira Li ◽

...

Keyword(s):

Critical Role ◽

Gene Expression Signature ◽

Endothelial Activation ◽

Tumor Vascularization ◽

Angiogenic Therapy ◽

Mouse Glioma ◽

Novel Therapeutic ◽

Tumor Area

AbstractOne of the most prominent features of glioblastoma (GBM) is hyper-vascularization. Bone marrow-derived macrophages are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs) which are thought to provide a critical role in tumor neo-vascularization. However, the mechanisms by which GAMs regulate endothelial cells (ECs) in the process of tumor vascularization and response to anti-angiogenic therapy (AATx) is not well-understood. Here we show that GBM cells secrete IL-8 and CCL2 which stimulate GAMs to produce TNFα. Subsequently, TNFα induces a distinct gene expression signature of activated ECs including VCAM-1, ICAM-1, CXCL5, and CXCL10. Inhibition of TNFα blocks GAM-induced EC activation both in vitro and in vivo and improve survival in mouse glioma models. Importantly we show that high TNFα expression predicts worse response to Bevacizumab in GBM patients. We further demonstrated in mouse model that treatment with B20.4.1.1, the mouse analog of Bevacizumab, increased macrophage recruitment to the tumor area and correlated with upregulated TNFα expression in GAMs and increased EC activation, which may be responsible for the failure of AATx in GBMs. These results suggest TNFα is a novel therapeutic that may reverse resistance to AATx. Future clinical studies should be aimed at inhibiting TNFα as a concurrent therapy in GBMs.

Download Full-text

TMOD-31. AN ORGANOTYPIC TISSUE PLATFORM TO BRIDGE IN VITRO AND IN VIVO ASSAYS FOR BRAIN CANCER TREATMENT

Neuro-Oncology ◽

10.1093/neuonc/noab196.892 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi222-vi222

Author(s):

Breanna Mann ◽

Noah Bell ◽

Denise Dunn ◽

Scott Floyd ◽

Shawn Hingtgen ◽

...

Keyword(s):

Cell Lines ◽

Brain Cancer ◽

Brain Slice ◽

Brain Slices ◽

In Vitro Assays ◽

Preclinical Model ◽

Short Period ◽

The Brain

Abstract Brain cancers remain one of the greatest medical challenges. The lack of experimentally tractable models that recapitulate brain structure/function represents a major impediment. Platforms that enable functional testing in high-fidelity models are urgently needed to accelerate the identification and translation of therapies to improve outcomes for patients suffering from brain cancer. In vitro assays are often too simple and artificial while in vivo studies can be time-intensive and complicated. Our live, organotypic brain slice platform can be used to seed and grow brain cancer cell lines, allowing us to bridge the existing gap in models. These tumors can rapidly establish within the brain slice microenvironment, and morphologic features of the tumor can be seen within a short period of time. The growth, migration, and treatment dynamics of tumors seen on the slices recapitulate what is observed in vivo yet is missed by in vitro models. Additionally, the brain slice platform allows for the dual seeding of different cell lines to simulate characteristics of heterogeneous tumors. Furthermore, live brain slices with embedded tumor can be generated from tumor-bearing mice. This method allows us to quantify tumor burden more effectively and allows for treatment and retreatment of the slices to understand treatment response and resistance that may occur in vivo. This brain slice platform lays the groundwork for a new clinically relevant preclinical model which provides physiologically relevant answers in a short amount of time leading to an acceleration of therapeutic translation.

Download Full-text

c-Jun N-Terminal Kinase Activation of Activator Protein-1 Underlies Homologous Regulation of the Gonadotropin-Releasing Hormone Receptor Gene in αT3-1 Cells

Endocrinology ◽

10.1210/en.2002-220784 ◽

2003 ◽

Vol 144 (3) ◽

pp. 839-849 ◽

Cited By ~ 24

Author(s):

Buffy S. Ellsworth ◽

Brett R. White ◽

Ann T. Burns ◽

Brian D. Cherrington ◽

Annette M. Otis ◽

...

Keyword(s):

Gene Expression ◽

Protein Kinase ◽

Cell Model ◽

Receptor Gene ◽

Critical Role ◽

Dominant Negative ◽

Activator Protein 1 ◽

Activator Protein

Reproductive function is dependent on the interaction between GnRH and its cognate receptor found on gonadotrope cells of the anterior pituitary gland. GnRH activation of the GnRH receptor (GnRHR) is a potent stimulus for increased expression of multiple genes including the gene encoding the GnRHR itself. Thus, homologous regulation of the GnRHR is an important mechanism underlying gonadotrope sensitivity to GnRH. Previously, we have found that GnRH induction of GnRHR gene expression in αT3-1 cells is partially mediated by protein kinase C activation of a canonical activator protein-1 (AP-1) element. In contrast, protein kinase A and a cAMP response element-like element have been implicated in mediating the GnRH response of the GnRHR gene using a heterologous cell model (GGH3). Herein we find that selective removal of the canonical AP-1 site leads to a loss of GnRH regulation of the GnRHR promoter in transgenic mice. Thus, an intact AP-1 element is necessary for GnRH responsiveness of the GnRHR gene both in vitro and in vivo. Based on in vitro analyses, GnRH appeared to enhance the interaction of JunD, FosB, and c-Fos at the GnRHR AP-1 element. Although enhanced binding of cFos reflected an increase in gene expression, GnRH appeared to regulate both FosB and JunD at a posttranslational level. Neither overexpression of a constitutively active Raf-kinase nor pharmacological blockade of GnRH-induced ERK activation eliminated the GnRH response of the GnRHR promoter. GnRH responsiveness was, however, lost in αT3-1 cells that stably express a dominant-negative c-Jun N-terminal kinase (JNK) kinase, suggesting a critical role for JNK in mediating GnRH regulation of the GnRHR gene. Consistent with this possibility, we find that the ability of forskolin and membrane-permeable forms of cAMP to inhibit the GnRH response of the GnRHR promoter is associated with a loss of both JNK activation and GnRH-mediated recruitment of the primary AP-1-binding components.

Download Full-text

Protein arginine methyltransferase 6-dependent gene expression and splicing: association with breast cancer outcomes

Endocrine Related Cancer ◽

10.1530/erc-12-0100 ◽

2012 ◽

Vol 19 (4) ◽

pp. 509-526 ◽

Cited By ~ 16

Author(s):

Dennis H Dowhan ◽

Matthew J Harrison ◽

Natalie A Eriksson ◽

Peter Bailey ◽

Michael A Pearen ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Alternative Splicing ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Gene Expression Signature ◽

Human Breast ◽

Arginine Methyltransferase ◽

Breast Tumours

Protein arginine methyltransferase-6 (PRMT6) regulates steroid-dependent transcription and alternative splicing and is implicated in endocrine system development and function, cell death, cell cycle, gene expression and cancer. Despite its role in these processes, little is known about its function and cellular targets in breast cancer. To identify novel gene targets regulated by PRMT6 in breast cancer cells, we used a combination of small interfering RNA and exon-specific microarray profilingin vitrocoupled toin vivovalidation in normal breast and primary human breast tumours. This approach, which allows the examination of genome-wide changes in individual exon usage and total transcript levels, demonstrated thatPRMT6knockdown significantly affected i) the transcription of 159 genes and ii) alternate splicing of 449 genes. ThePRMT6-dependent transcriptional and alternative splicing targets identifiedin vitrowere validated in human breast tumours. Using the list of genes differentially expressed between normal andPRMT6knockdown cells, we generated aPRMT6-dependent gene expression signature that provides an indication of PRMT6 dysfunction in breast cancer cells. Interrogation of several well-studied breast cancer microarray expression datasets with thePRMT6gene expression signature demonstrated that PRMT6 dysfunction is associated with better overall relapse-free and distant metastasis-free survival in the oestrogen receptor (ER (ESR1)) breast cancer subgroup. These results suggest that dysregulation ofPRMT6-dependent transcription and alternative splicing may be involved in breast cancer pathophysiology and the molecular consequences identifying a unique and informative biomarker profile.

Download Full-text

Macrophage Modification Strategies for Efficient Cell Therapy

Cells ◽

10.3390/cells9061535 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1535 ◽

Cited By ~ 5

Author(s):

Anastasiya S. Poltavets ◽

Polina A. Vishnyakova ◽

Andrey V. Elchaninov ◽

Gennady T. Sukhikh ◽

Timur Kh. Fatkhudinov

Keyword(s):

Gene Expression ◽

Gene Editing ◽

Target Selection ◽

Model Systems ◽

Attractive Therapeutic Target ◽

Specific Alteration ◽

Inflammatory Phenotypes ◽

Vector Delivery

Macrophages, important cells of innate immunity, are known for their phagocytic activity, capability for antigen presentation, and flexible phenotypes. Macrophages are found in all tissues and therefore represent an attractive therapeutic target for the treatment of diseases of various etiology. Genetic programming of macrophages is an important issue of modern molecular and cellular medicine. The controllable activation of macrophages towards desirable phenotypes in vivo and in vitro will provide effective treatments for a number of inflammatory and proliferative diseases. This review is focused on the methods for specific alteration of gene expression in macrophages, including the controllable promotion of the desired M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes in certain pathologies or model systems. Here we review the strategies of target selection, the methods of vector delivery, and the gene editing approaches used for modification of macrophages.

Download Full-text

Glucocorticoid receptor action in metabolic and neuronal function

F1000Research ◽

10.12688/f1000research.11375.1 ◽

2017 ◽

Vol 6 ◽

pp. 1208 ◽

Cited By ~ 19

Author(s):

Michael J. Garabedian ◽

Charles A. Harris ◽

Freddy Jeanneteau

Keyword(s):

Gene Expression ◽

Glucocorticoid Receptor ◽

Metabolic Diseases ◽

Cell Types ◽

Health And Disease ◽

And Behavior ◽

External Signals ◽

The Brain

Glucocorticoids via the glucocorticoid receptor (GR) have effects on a variety of cell types, eliciting important physiological responses via changes in gene expression and signaling. Although decades of research have illuminated the mechanism of how this important steroid receptor controls gene expression using in vitro and cell culture–based approaches, how GR responds to changes in external signals in vivo under normal and pathological conditions remains elusive. The goal of this review is to highlight recent work on GR action in fat cells and liver to affect metabolism in vivo and the role GR ligands and receptor phosphorylation play in calibrating signaling outputs by GR in the brain in health and disease. We also suggest that both the brain and fat tissue communicate to affect physiology and behavior and that understanding this “brain-fat axis” will enable a more complete understanding of metabolic diseases and inform new ways to target them.

Download Full-text

Genomic characterization of preclinical models derived from primary and metastatic sites from rapid autopsy patients in PDMR.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13506 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13506-e13506

Author(s):

Li Chen ◽

Rajesh Patidar ◽

Biswajit Das ◽

Yvonne A Evrard ◽

Chris Alan Karlovich ◽

...

Keyword(s):

Gene Expression ◽

Gene Expression Data ◽

Driver Mutations ◽

Tumor Evolution ◽

Preclinical Model ◽

Expression Data ◽

Preclinical Models ◽

Rapid Autopsy ◽

Metastatic Sites ◽

Pdx Models

e13506 Background: The National Cancer Institute has developed a repository of preclinical models [Patient-Derived Models Repository (NCI PDMR, https://pdmr.cancer.gov )] including patient derived xenografts (PDXs), organoids (PDOrgs) and in vitro tumor cultures (PDCs) from patients with solid tumor cancer histologies. A subset of these preclinical models is derived from post-mortem collections from rapid autopsies representing the end point in disease progression. Clinical annotations and genomic datasets associated with these models provide a unique opportunity to study tumor evolution, mechanistic insights into the metastatic process, and treatment resistance. Methods: To date, 43 PDXs, 21 PDCs, and 23 PDOrgs using rapid autopsy specimens from 8 primary and 35 metastatic sites of 18 patients have been developed by the Biological Testing Branch (DTP, DCTD, NCI Frederick, MD) for the PDMR. Whole exome (WES) and total transcriptome (RNASeq) data were processed to generate mutation, copy number alteration (CNA) and gene expression data. Multi-model lineage trees were reconstructed based on putative somatic variants for all the models derived from all patients. The fraction of the genome affected by CNA was compared both within and across PDX models. Results: Most of the rapid autopsy PDX models (32/43) are derived from pancreatic adenocarcinoma (PAAD) patients (13/18), with metastatic specimens originating from sites including liver, colon, omentum, and lung. Driver mutations are present in all preclinical model specimens derived from the same patient. For instance, KRAS p.G12D is present in all patient-derived model specimens derived from PAAD patient 521955. The fraction of the genome affected by CNA remains stable within a PDX model across passages (n = 24, mean = 6.39%, sd = 5.90%). However, we found that this increased when comparing PDX models derived from metastatic sites versus the primary site (n = 19, mean = 16.92%, sd = 10.46%). This indicates presence of tumor heterogeneity between metastatic and primary sites. The lineage tree for models from patient 521955 indicates that one liver metastasis has a unique seeding event compared to the other 4 metastatic sites. Unsupervised clustering analysis on gene expression data also confirms the observed tumor site relationships. Conclusions: Our data demonstrate the potential use of these preclinical models available from the NCI PDMR. These models provide a unique resource for preclinical studies in tumor evolution, metastatic spread mediators, and drug resistance.

Download Full-text

Molecular characterization of neuroendocrine bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.561 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 561-561

Author(s):

Woonyoung Choi ◽

Jean H. Hoffman-Censits ◽

Megan Fong ◽

Noah M. Hahn ◽

Eva Comperat ◽

...

Keyword(s):

Gene Expression ◽

Bladder Cancer ◽

Gene Expression Signature ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Molecular Features ◽

Pathway Gene ◽

Immune Pathway ◽

Muscle Invasive ◽

Whole Transcriptome

561 Background: Neuroendocrine bladder cancer (NEBC) is a rare and aggressive variant that is associated with poor survival outcomes. Because NEBC is rare, the molecular features of NEBC remain poorly characterized. Therefore, we characterized NEBC at the molecular level to understand the underlying biology and identify novel therapeutic targets. Methods: Whole transcriptome RNAseq was performed on FFPE cores from 24 NEBCs and 51 conventional muscle-invasive bladder cancers (MIBCs) from Tenon Hospital in Paris. Results: Unsupervised cluster analysis of 75 tumors generated 2 distinct clusters that separated NEBCs from MIBCs. The NEBC tumors were strongly enriched with biomarkers for the characteristic of neuroendocrine or small cell malignancies, including DLL3, SOX2, and EZH2. In addition, E2F1 pathway is significantly enriched due to the impair of RB/p53 pathways. Further, the NEBCs were enriched with the TCGA’s neuronal differentiation genes that were associated with high response rates in patients treated in atezolizumab (anti-PDL1) within the context of the ImVigor 210 trial. Nevertheless, the NEBCs were characterized by suppressed immune pathway gene expression signatures, such as the Th1 pathway, effector T cell lymphocyte, and IFNg that are usually highly enriched in tumors that are sensitive to immune checkpoint blockade. Of candidate mechanisms, the suppressed TGFbpathway activity observed in the NEBCs was the most obvious explanation for sensitivity to checkpoint blockade. Conclusions: NEBCs are distinct from conventional MIBCs by gene expression signature. They are also characterized by overexpression of canonical neuroendocrine markers and inhibition of TGFb pathway activity.

Download Full-text