In Vivo Posttranslational Modifications of the High Mobility Group A1a Proteins in Breast Cancer Cells of Differing Metastatic Potential†

Biochemistry ◽  
2004 ◽  
Vol 43 (36) ◽  
pp. 11500-11515 ◽  
Author(s):  
Dale D. Edberg ◽  
James E. Bruce ◽  
William F. Siems ◽  
Raymond Reeves
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Posttranslational Modifications ◽  
Breast Cancer Cells ◽  
High Mobility ◽  
Metastatic Potential ◽  
High Mobility Group

750 Malat1 lncRNA controls metastatic reactivation of dormant breast cancer by immune evasion

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A799-A799
Author(s):  
Dhiraj Kumar ◽  
Sreeharsha Gurrapu ◽  
Hyunho Han ◽  
Yan Wang ◽  
Seongyeon Bae ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Single Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Breast Cancer Cells ◽  
Metastatic Potential ◽  
Rna Seq

BackgroundLong non-coding RNAs (lncRNAs) are involved in various biological processes and diseases. Malat1 (metastasis-associated lung adenocarcinoma transcript 1), also known as Neat2, is one of the most abundant and highly conserved nuclear lncRNAs. Several studies have shown that the expression of lncRNA Malat1 is associated with metastasis and serving as a predictive marker for various tumor progression. Metastatic relapse often develops years after primary tumor removal as a result of disseminated tumor cells undergoing a period of latency in the target organ.1–4 However, the correlation of tumor intrinsic lncRNA in regulation of tumor dormancy and immune evasion is largely unknown.MethodsUsing an in vivo screening platform for the isolation of genetic entities involved in either dormancy or reactivation of breast cancer tumor cells, we have identified Malat1 as a positive mediator of metastatic reactivation. To functionally uncover the role of Malat1 in metastatic reactivation, we have developed a knock out (KO) model by using paired gRNA CRISPR-Cas9 deletion approach in metastatic breast and other cancer types, including lung, colon and melanoma. As proof of concept we also used inducible knockdown system under in vivo models. To delineate the immune micro-environment, we have used 10X genomics single cell RNA-seq, ChIRP-seq, multi-color flowcytometry, RNA-FISH and immunofluorescence.ResultsOur results reveal that the deletion of Malat1 abrogates the tumorigenic and metastatic potential of these tumors and supports long-term survival without affecting their ploidy, proliferation, and nuclear speckles formation. In contrast, overexpression of Malat1 leads to metastatic reactivation of dormant breast cancer cells. Moreover, the loss of Malat1 in metastatic cells induces dormancy features and inhibits cancer stemness. Our RNA-seq and ChIRP-seq data indicate that Malat1 KO downregulates several immune evasion and stemness associated genes. Strikingly, Malat1 KO cells exhibit metastatic outgrowth when injected in T cells defective mice. Our single-cell RNA-seq cluster analysis and multi-color flow cytometry data show a greater proportion of T cells and reduce Neutrophils infiltration in KO mice which indicate that the immune microenvironment playing an important role in Malat1-dependent immune evasion. Mechanistically, loss of Malat1 is associated with reduced expression of Serpinb6b, which protects the tumor cells from cytotoxic killing by the T cells. Indeed, overexpression of Serpinb6b rescued the metastatic potential of Malat1 KO cells by protecting against cytotoxic T cells.ConclusionsCollectively, our data indicate that targeting this novel cancer-cell-initiated domino effect within the immune system represents a new strategy to inhibit tumor metastatic reactivation.Trial RegistrationN/AEthics ApprovalFor all the animal studies in the present study, the study protocols were approved by the Institutional Animal Care and Use Committee(IACUC) of UT MD Anderson Cancer Center.ConsentN/AReferencesArun G, Diermeier S, Akerman M, et al., Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss. Genes Dev 2016 Jan 1;30(1):34–51.Filippo G. Giancotti, mechanisms governing metastatic dormancy and reactivation. Cell 2013 Nov 7;155(4):750–764.Gao H, Chakraborty G, Lee-Lim AP, et al., The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 2012b;150:764–779.Gao H, Chakraborty G, Lee-Lim AP, et al., Forward genetic screens in mice uncover mediators and suppressors of metastatic reactivation. Proc Natl Acad Sci U S A 2014 Nov 18; 111(46): 16532–16537.

scholarly journals Cancer-associated fibroblasts induce high mobility group box 1 and contribute to resistance to doxorubicin in breast cancer cells

BMC Cancer ◽  
2014 ◽  
Vol 14 (1) ◽  
Author(s):  
Kamolporn Amornsupak ◽  
Tonkla Insawang ◽  
Peti Thuwajit ◽  
Pornchai O-Charoenrat ◽  
Suzanne A Eccles ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
High Mobility ◽  
High Mobility Group ◽  
Cancer Associated Fibroblasts ◽  
Resistance To Doxorubicin

scholarly journals Homing Choices of Breast Cancer Cells Revealed by Tissue Specific Invasion and Extravasation Lab-on-a-chip Platforms

2020 ◽  
Author(s):  
Burcu Firatligil-Yildirir ◽  
Gizem Bati-Ayaz ◽  
Ismail Tahmaz ◽  
Muge Bilgen ◽  
Devrim Pesen-Okvur ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Lab On A Chip ◽  
Metastatic Potential ◽  
Diagnostic Tools ◽  
Breast Cancer Patients ◽  
Tissue Specific ◽  
Non Invasive

AbstractMetastasis is one of the major obstacles for breast cancer patients. Limitations of current models demand the development of novel platforms to predict metastatic potential and homing choices of cancer cells. Here, two novel Lab-on-a-chip (LOC) platforms, invasion/chemotaxis (IC-chip) and extravasation (EX-chip), are presented for the quantitative assessment of invasion and extravasation, towards specific tissues. On IC-chip, invasive MDA-MB-231, but not non-invasive MCF-7 breast cancer cells invaded lung and liver microenvironments. Lung-specific but not bone-specific MDA-MB-231 clones efficiently invaded lung microenvironment, stressing ability of IC-chip to demonstrate different in vivo metastatic behaviors. On EX-chip, MDA-MB-231 cells extravasated more into the lung microenvironment compared to the liver and breast highlighting the potency of the platform to mimic in vivo homing choices. Overall, this study presents IC-chip and EX-chip that can determine tissue-specific invasion and extravasation potentials of cancer cells providing the groundwork for novel diagnostic tools to predict metastasis risk.

scholarly journals GRP78 promotes stemness in normal and neoplastic cells

2019 ◽  
Author(s):  
Clay Conner ◽  
Tyson W. Lager ◽  
Ian H. Guldner ◽  
Min-Zu Wu ◽  
Yuriko Hishida ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Surface ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Embryonic Stem ◽  
Metastatic Potential ◽  
Cellular Functions ◽  
Normal Tissues ◽  
Aggressive Cancer

ABSTRACTReliable approaches to identify stem cell mechanisms that mediate aggressive cancer could have great therapeutic value, based on the growing evidence of embryonic signatures in metastatic cancers. However, how to best identify and target stem-like mechanisms aberrantly acquired by cancer cells has been challenging. We harnessed the power of reprogramming to examine GRP78, a chaperone protein generally restricted to the endoplasmic reticulum in normal tissues, but which is expressed on the cell surface of human embryonic stem cells and many cancer types. We have discovered that (1) cell surface GRP78 (sGRP78) is expressed on iPSCs and is important in reprogramming, (2) sGRP78 promotes cellular functions in both pluripotent and breast cancer cells (3) overexpression of GRP78 in breast cancer cells leads to an induction of a CD24-/CD44+ tumor initiating cell (TIC) population (4) sGRP78+ breast cancer cells are enriched for stemness genes and appear to be a subset of TICs (5) sGRP78+ breast cancer cells show an enhanced ability to seed metastatic organ sites in vivo. These collective findings show that GRP78 has important functions in regulating both pluripotency and oncogenesis, and suggest that sGRP78 marks a stem-like population in breast cancer cells that has increased metastatic potential in vivo.

scholarly journals High-mobility group A1a protein regulates Ras/ERK signaling in MCF-7 human breast cancer cells

Oncogene ◽  
2004 ◽  
Vol 23 (3) ◽  
pp. 777-785 ◽  
Author(s):  
Nathan R Treff ◽  
Derek Pouchnik ◽  
Gregory A Dement ◽  
Rachel L Britt ◽  
Raymond Reeves
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
High Mobility ◽  
High Mobility Group ◽  
Erk Signaling ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Mcf 7
Sign in / Sign up

Export Citation Format

Share Document