scholarly journals Cell non-autonomous interactions during non-immune stromal progression in the breast tumor microenvironment

2019 ◽  
Author(s):  
Raditya Utama ◽  
Anja Bastian ◽  
Narayanan Sadagopan ◽  
Ying Jin ◽  
Eric Antoniou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Primary Tumor ◽  
Breast Tumor ◽  
Expression Profiles ◽  
Metastatic Tumor ◽  
Normal Breast ◽  
Epithelial Tissue ◽  
Mesenchymal Transition ◽  
Nis Gene

SummaryThe breast tumor microenvironment of primary and metastatic sites is a complex milieu of differing cell populations, consisting of tumor cells and the surrounding stroma. Despite recent progress in delineating the immune component of the stroma, the genomic expression landscape of the non-immune stroma (NIS) population and their role in mediating cancer progression and informing effective therapies are not well understood. Here we obtained 52 cell-sorted NIS and epithelial tissue samples across 37 patients from i) normal breast, ii) normal breast adjacent to primary tumor, iii) primary tumor, and iv) metastatic tumor sites. Deep RNA-seq revealed diverging gene expression profiles as the NIS evolves from normal to metastatic tumor tissue, with intra-patient normal-primary variation comparable to inter-patient variation. Significant expression changes between normal and adjacent normal tissue support the notion of a cancer field effect, but extended out to the NIS. Most differentially expressed protein-coding genes and lncRNAs were found to be associated with pattern formation, embryogenesis, and the epithelial-mesenchymal transition. We validated the protein expression changes of a novel candidate gene, C2orf88, by immunohistochemistry staining of representative tissues. Significant mutual information between epithelial ligand and NIS receptor gene expression, across primary and metastatic tissue, suggests a unidirectional model of molecular signaling between the two tissues. Furthermore, survival analyses of 827 luminal breast tumor samples demonstrated the predictive power of the NIS gene expression to inform clinical outcomes. Together, these results highlight the evolution of NIS gene expression in breast tumors and suggest novel therapeutic strategies targeting the microenvironment.

scholarly journals P02.10 FocuSCOPE: a single cell, multi-omics solution to simultaneously analyze tumor variants and microenvironment

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A12.1-A12
Author(s):  
Y Arjmand Abbassi ◽  
N Fang ◽  
W Zhu ◽  
Y Zhou ◽  
Y Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
High Throughput ◽  
Immune Cells ◽  
Genetic Variants ◽  
Expression Profiles ◽  
Single Cells ◽  
Gene Expression Profiles ◽  
Single Cell Sequencing

Recent advances of high-throughput single cell sequencing technologies have greatly improved our understanding of the complex biological systems. Heterogeneous samples such as tumor tissues commonly harbor cancer cell-specific genetic variants and gene expression profiles, both of which have been shown to be related to the mechanisms of disease development, progression, and responses to treatment. Furthermore, stromal and immune cells within tumor microenvironment interact with cancer cells to play important roles in tumor responses to systematic therapy such as immunotherapy or cell therapy. However, most current high-throughput single cell sequencing methods detect only gene expression levels or epigenetics events such as chromatin conformation. The information on important genetic variants including mutation or fusion is not captured. To better understand the mechanisms of tumor responses to systematic therapy, it is essential to decipher the connection between genotype and gene expression patterns of both tumor cells and cells in the tumor microenvironment. We developed FocuSCOPE, a high-throughput multi-omics sequencing solution that can detect both genetic variants and transcriptome from same single cells. FocuSCOPE has been used to successfully perform single cell analysis of both gene expression profiles and point mutations, fusion genes, or intracellular viral sequences from thousands of cells simultaneously, delivering comprehensive insights of tumor and immune cells in tumor microenvironment at single cell resolution.Disclosure InformationY. Arjmand Abbassi: None. N. Fang: None. W. Zhu: None. Y. Zhou: None. Y. Chen: None. U. Deutsch: None.

scholarly journals Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment

2019 ◽  
Vol 11 (501) ◽  
pp. eaav7816 ◽  
Author(s):  
Rachael M. Zemek ◽  
Emma De Jong ◽  
Wee Loong Chin ◽  
Iona S. Schuster ◽  
Vanessa S. Fear ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Nk Cells ◽  
Immune Checkpoint ◽  
Expression Profiles ◽  
Gene Expression Signature ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Poly I:C ◽  
Mouse Strains

Cancer immunotherapy using antibodies that target immune checkpoints has delivered outstanding results. However, responses only occur in a subset of patients, and it is not fully understood what biological processes determine an effective outcome. This lack of understanding hinders the development of rational combination treatments. We set out to define the pretreatment microenvironment associated with an effective outcome by using the fact that inbred mouse strains bearing monoclonal cancer cell line–derived tumors respond in a dichotomous manner to immune checkpoint blockade (ICB). We compared the cellular composition and gene expression profiles of responsive and nonresponsive tumors from mice before ICB and validated the findings in cohorts of patients with cancer treated with ICB antibodies. We found that responsive tumors were characterized by an inflammatory gene expression signature consistent with up-regulation of signal transducer and activator of transcription 1 (STAT1) and Toll-like receptor 3 (TLR3) signaling and down-regulation of interleukin-10 (IL-10) signaling. In addition, responsive tumors had more infiltrating-activated natural killer (NK) cells, which were necessary for response. Pretreatment of mice with large established tumors using the STAT1-activating cytokine interferon-γ (IFNγ), the TLR3 ligand poly(I:C), and an anti–IL-10 antibody sensitized tumors to ICB by attracting IFNγ-producing NK cells into the tumor, resulting in increased cure rates. Our results identify a pretreatment tumor microenvironment that predicts response to ICB, which can be therapeutically attained. These data suggest a biomarker-driven approach to patient management to establish whether a patient would benefit from treatment with sensitizing therapeutics before ICB.

scholarly journals An unsupervised feature extraction and selection strategy for identifying epithelial-mesenchymal transition state metrics in breast cancer and melanoma

2019 ◽  
Author(s):  
David J. Klinke ◽  
Arezo Torang
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Tumor Microenvironment ◽  
Epithelial Mesenchymal Transition ◽  
Cell Phenotype ◽  
Holistic View ◽  
Mesenchymal Transition ◽  
Feature Extraction And Selection ◽  
Cellular Context ◽  
Immune Contexture

Digital cytometry is opening up new avenues to better understand the heterogeneous cell types present within the tumor microenvironment. While the focus is towards elucidating immune and stromal cells as clinical correlates, there is still a need to better understand how a change in tumor cell phenotype, such as the epithelial-mesenchymal transition, influences the immune contexture. To complement existing digital cytometry methods, our objective was to develop an unsupervised gene signature capturing a change in differentiation state that is tailored to the specific cellular context of breast cancer and melanoma, as a illustrative example. Towards this aim, we used principal component analysis coupled with resampling to develop unsupervised gene expression-based state metrics specific for the cellular context that characterize the state of cellular differentiation within an epithelial to mesenchymal-like state space and independently correlate with metastatic potential. First developed using cell line data, the orthogonal state metrics were refined to exclude the contributions of normal fibroblasts and to provide tissue-level state estimates based on bulk tissue RNA-seq measures. The resulting gene expression-based metrics for differentiation state aim to inform a more holistic view of how the malignant cell phenotype influences the immune contexture within the tumor microenvironment.

Angiogenic gene expression in primary neuroendocrine tumors and their metastases.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 200-200
Author(s):  
Tanja Milosavljevic ◽  
Michael Anthony Hall ◽  
Luis Del Valle ◽  
Elise Juge ◽  
Jovanny Zabaleta ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Neuroendocrine Tumors ◽  
Primary Tumor ◽  
Expression Profiles ◽  
Current Treatment ◽  
Tumor Site ◽  
Tissue Samples ◽  
Multiple Tumor ◽  
Gene And Protein Expression

200 Background: Neuroendocrine tumors (NETs) are neoplasms arising from the cells of the nervous, endocrine and hormonal systems. They most commonly originate in the small bowel (SB) and frequently metastasize to the lymph nodes (LNs) and/or liver (LV). Current treatment of metastatic NETs involves a variety of approaches including antiangiogenic therapies. Our group demonstrated that there are significant histologic and functional differences between the primary NETs and their nodal or organ metastases. We hypothesized that sampling of multiple tumor sites within the same individual will reveal differential expression profiles of angiogenesis-related genes. Methods: Tissue-matched normal and tumor tissue samples were obtained from patients with well differentiated NETs who underwent simultaneous removal of their primary tumor, nodal, and organ metastasis. High quality RNA was extracted from each tumor site using TRIzol and RNeasy Mini kit. Gene expression of 28 well-documented angiogenesis-related genes was assessed using Custom Quantitative RT-PCR array. These gene expression trends were validated by Illumina microarray and TaqMan analysis. Immunohistochemistry (IHC) staining was performed using Avidin-Biotin-Peroxidase complex, with the markers: SSTR2 and FGFR3. Results: Normal SB, LN, and LV gene expression of 28 genes was compared to that of the tumor sample at each tumor site [4-fold change, p ≤ 0.01]. A consistent up-regulation of SSTR2 and SSTR1 was seen in 18/24 (75%) samples. Up-regulation of FGFR3 and SSTR5 was observed in 13/24 (50%) of tumors. TGFA and IGF were consistently down-regulated in 12/24 (50%) and 10/24 (42%) of tumor samples, respectively. Six genes expression trends were validated by TaqMan analysis and Illumina microarray analysis. IHC staining revealed higher SSTR2 and FGFR3 protein expression in all three tumor sites compared to the control. Conclusions: Expression of angiogenesis-related genes varies between the primary tumor (SB) and metastatic sites (LV, LN) within the same individual. We found a positive correlation between SSTR2 and FGFR3 gene and protein expression levels in all three tumor sites.

scholarly journals Humanization of the Prostate Microenvironment Reduces Homing of PC3 Prostate Cancer Cells to Human Tissue-Engineered Bone

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 438 ◽  
Author(s):  
Jacqui McGovern ◽  
Abbas Shafiee ◽  
Ferdinand Wagner ◽  
Christoph Lahr ◽  
Marietta Landgraf ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Primary Tumor ◽  
Metastatic Tumor ◽  
Tumor Burden ◽  
Prostate Tissue ◽  
Homing Behavior ◽  
Nsg Mice ◽  
Species Specific

The primary tumor microenvironment is inherently important in prostate cancer (PCa) initiation, growth and metastasis. However, most current PCa animal models are based on the injection of cancer cells into the blood circulation and bypass the first steps of the metastatic cascade, hence failing to investigate the influence of the primary tumor microenvironment on PCa metastasis. Here, we investigated the spontaneous metastasis of PC3 human PCa cells from humanized prostate tissue, containing cancer-associated fibroblasts (CAFs) and prostate lymphatic and blood vessel endothelial cells (BVECs), to humanized tissue-engineered bone constructs (hTEBCs) in NOD-SCID IL2Rγnull (NSG) mice. The hTEBC formed a physiologically mature organ bone which allowed homing of metastatic PCa cells. Humanization of prostate tissue had no significant effect on the tumor burden at the primary site over the 4 weeks following intraprostatic injection, yet reduced the incidence and burden of metastases in the hTEBC. Spontaneous PCa metastases were detected in the lungs and spleen with no significant differences between the humanized and non-humanized prostate groups. A significantly greater metastatic tumor burden was observed in the liver when metastasis occurred from the humanized prostate. Together, our data suggests that the presence of human-derived CAFs and BVECs in the primary PCa microenvironment influences selectively the metastatic and homing behavior of PC3 cells in this model. Our orthotopic and humanized PCa model developed via convergence of cancer research and tissue engineering concepts provides a platform to dissect mechanisms of species-specific PCa bone metastasis and to develop precision medicine strategies.

scholarly journals Altered Expression of Secreted Mediator Genes That Mediate Aggressive Breast Cancer Metastasis to Distant Organs

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2641
Author(s):  
Aparna Maiti ◽  
Ichiro Okano ◽  
Masanori Oshi ◽  
Maiko Okano ◽  
Wanqing Tian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Primary Tumor ◽  
Cancer Metastasis ◽  
Metastatic Tumor ◽  
Breast Tumors ◽  
Metastatic Lesion ◽  
Breast Cancer Metastasis ◽  
Sequencing Data ◽  
Altered Expression ◽  
Metastatic Variant

Heterogeneity is the characteristic of breast tumors, making it difficult to understand the molecular mechanism. Alteration of gene expression in the primary tumor versus the metastatic lesion remains challenging for getting any specific targeted therapy. To better understand how gene expression profile changes during metastasis, we compare the primary tumor and distant metastatic tumor gene expression using primary breast tumors compared with its metastatic variant in animal models. Our RNA sequencing data from cells revealed that parental cell and the metastatic variant cell are different in gene expression while gene signature significantly altered during metastasis to distant organs than primary breast tumors. We found that secreted mediators encoding genes (ANGPTL7, MMP3, LCN2, S100A8, and ESM1) are correlated with poor prognosis in the clinical setting as divulged from METABRIC and TCGA-BRCA cohort data analysis.

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