High and ultra‐high definition of infrared spectral histopathology gives an insight into chemical environment of lung metastases in breast cancer

Although metastatic disease is the primary cause of mortality in cancer patients, the mechanisms leading to overwhelming metastatic burden are still incompletely understood. Metastases are the endpoint of a series of multi-step events involving cancer cell intravasation, dissemination to distant organs, and outgrowth to metastatic colonies. Here we show, for the first-time, that breast cancer cells do not solely disseminate to distant organs from primary tumors and metastatic nodules in the lymph nodes, but also do so from lung metastases. Thus, our findings indicate that metastatic dissemination could continue even after the removal of the primary tumor. Provided that the re-disseminated cancer cells initiate growth upon arrival to distant sites, cancer cell re-dissemination from metastatic foci could be one of the crucial mechanisms leading to overt metastases and patient demise. Therefore, the development of new therapeutic strategies to block cancer cell re-dissemination would be crucial to improving survival of patients with metastatic disease.

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Multi-omics data integration reveals correlated regulatory features of triple negative breast cancer

Molecular Omics ◽

10.1039/d1mo00117e ◽

2021 ◽

Author(s):

Kevin Chappell ◽

Kanishka Manna ◽

Charity L. Washam ◽

Stefan Graw ◽

Duah Alkam ◽

...

Keyword(s):

Breast Cancer ◽

Data Integration ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Biological Pathways ◽

Omics Data ◽

Insight Into ◽

Omics Data Integration

Multi-omics data integration of triple negative breast cancer (TNBC) provides insight into biological pathways.

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Iron-Bound Lipocalin-2 from Tumor-Associated Macrophages Drives Breast Cancer Progression Independent of Ferroportin

Metabolites ◽

10.3390/metabo11030180 ◽

2021 ◽

Vol 11 (3) ◽

pp. 180

Author(s):

Christina Mertens ◽

Matthias Schnetz ◽

Claudia Rehwald ◽

Stephan Grein ◽

Eiman Elwakeel ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Tumor Cells ◽

Cancer Progression ◽

Lung Metastases ◽

Expression Profiles ◽

The Cancer Genome Atlas ◽

Lipocalin 2 ◽

Tumor Associated Macrophages

Macrophages supply iron to the breast tumor microenvironment by enforced secretion of lipocalin-2 (Lcn-2)-bound iron as well as the increased expression of the iron exporter ferroportin (FPN). We aimed at identifying the contribution of each pathway in supplying iron for the growing tumor, thereby fostering tumor progression. Analyzing the expression profiles of Lcn-2 and FPN using the spontaneous polyoma-middle-T oncogene (PyMT) breast cancer model as well as mining publicly available TCGA (The Cancer Genome Atlas) and GEO Series(GSE) datasets from the Gene Expression Omnibus database (GEO), we found no association between tumor parameters and Lcn-2 or FPN. However, stromal/macrophage-expression of Lcn-2 correlated with tumor onset, lung metastases, and recurrence, whereas FPN did not. While the total iron amount in wildtype and Lcn-2−/− PyMT tumors showed no difference, we observed that tumor-associated macrophages from Lcn-2−/− compared to wildtype tumors stored more iron. In contrast, Lcn-2−/− tumor cells accumulated less iron than their wildtype counterparts, translating into a low migratory and proliferative capacity of Lcn-2−/− tumor cells in a 3D tumor spheroid model in vitro. Our data suggest a pivotal role of Lcn-2 in tumor iron-management, affecting tumor growth. This study underscores the role of iron for tumor progression and the need for a better understanding of iron-targeted therapy approaches.

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m6A-induced LINC00958 promotes breast cancer tumorigenesis via the miR-378a-3p/YY1 axis

Cell Death Discovery ◽

10.1038/s41420-020-00382-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Dongwen Rong ◽

Qian Dong ◽

Huajun Qu ◽

Xinna Deng ◽

Fei Gao ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Human Breast Cancer ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Human Breast ◽

Transcript Stability ◽

Rna Transcript ◽

Insight Into ◽

Competitive Endogenous Rna

AbstractIncreasing evidence demonstrates that long noncoding RNAs (lncRNAs) play critical roles in human breast cancer (BC) tumorigenesis. However, the mechanisms by which lncRNA and N6-methyladenosine (m6A) regulate BC tumorigenesis are still unclear. In the present research, LINC00958 was markedly overexpressed in BC tissue and cells, and LINC00958 upregulation promoted the tumor progression of BC cells. Mechanistically, m6A methyltransferase-like 3 (METTL3) gave rise to the upregulation of LINC00958 by promoting its RNA transcript stability. Moreover, LINC00958 acted as a competitive endogenous RNA for miR-378a-3p to promote YY1. Overall, these data provide novel insight into how m6A-mediated LINC00958 regulates BC tumorigenesis.

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Single-cell evaluation reveals shifts in the tumor-immune niches that shape and maintain aggressive lesions in the breast

Nature Communications ◽

10.1038/s41467-021-25240-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Vidya C. Sinha ◽

Amanda L. Rinkenbaugh ◽

Mingchu Xu ◽

Xinhui Zhou ◽

Xiaomei Zhang ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Mouse Model ◽

Transition State ◽

Tumor Cell ◽

Single Cell ◽

Tumor Cells ◽

Breast Lesions ◽

Aggressive Tumor ◽

Insight Into

AbstractThere is an unmet clinical need for stratification of breast lesions as indolent or aggressive to tailor treatment. Here, single-cell transcriptomics and multiparametric imaging applied to a mouse model of breast cancer reveals that the aggressive tumor niche is characterized by an expanded basal-like population, specialization of tumor subpopulations, and mixed-lineage tumor cells potentially serving as a transition state between luminal and basal phenotypes. Despite vast tumor cell-intrinsic differences, aggressive and indolent tumor cells are functionally indistinguishable once isolated from their local niche, suggesting a role for non-tumor collaborators in determining aggressiveness. Aggressive lesions harbor fewer total but more suppressed-like T cells, and elevated tumor-promoting neutrophils and IL-17 signaling, disruption of which increase tumor latency and reduce the number of aggressive lesions. Our study provides insight into tumor-immune features distinguishing indolent from aggressive lesions, identifies heterogeneous populations comprising these lesions, and supports a role for IL-17 signaling in aggressive progression.

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Trastuzumab Mechanism of Action; 20 Years of Research to Unravel a Dilemma

Cancers ◽

10.3390/cancers13143540 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3540

Author(s):

Hamid Maadi ◽

Mohammad Hasan Soheilifar ◽

Won-Shik Choi ◽

Abdolvahab Moshtaghian ◽

Zhixiang Wang

Keyword(s):

Breast Cancer ◽

Targeted Therapy ◽

Cancer Patients ◽

Mechanism Of Action ◽

Mechanisms Of Action ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Insight Into ◽

Positive Breast Cancer

Trastuzumab as a first HER2-targeted therapy for the treatment of HER2-positive breast cancer patients was introduced in 1998. Although trastuzumab has opened a new avenue to treat patients with HER2-positive breast cancer and other types of cancer, some patients are not responsive or become resistant to this treatment. So far, several mechanisms have been suggested for the mode of action of trastuzumab; however, the findings regarding these mechanisms are controversial. In this review, we aimed to provide a detailed insight into the various mechanisms of action of trastuzumab.

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Infrared spectral histopathology using haematoxylin and eosin (H&E) stained glass slides: a major step forward towards clinical translation

The Analyst ◽

10.1039/c6an02224c ◽

2017 ◽

Vol 142 (8) ◽

pp. 1258-1268 ◽

Cited By ~ 21

Author(s):

Michael J. Pilling ◽

Alex Henderson ◽

Jonathan H. Shanks ◽

Michael D. Brown ◽

Noel W. Clarke ◽

...

Keyword(s):

Diagnostic Tool ◽

Clinical Translation ◽

Great Promise ◽

Stained Glass ◽

Major Step ◽

Glass Slides ◽

Important Diagnostic Tool ◽

Infrared Spectral ◽

Spectral Histopathology

Infrared spectral histopathology has shown great promise as an important diagnostic tool, with the potential to complement current pathological methods.

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CD73 facilitates EMT progression and promotes lung metastases in triple-negative breast cancer

Scientific Reports ◽

10.1038/s41598-021-85379-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Nataliia Petruk ◽

Sanni Tuominen ◽

Malin Åkerfelt ◽

Jesse Mattsson ◽

Jouko Sandholm ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Epithelial Mesenchymal Transition ◽

Lung Metastases ◽

Vimentin Expression ◽

Mesenchymal Transition ◽

Cell Protrusion

AbstractCD73 is a cell surface ecto-5′-nucleotidase, which converts extracellular adenosine monophosphate to adenosine. High tumor CD73 expression is associated with poor outcome among triple-negative breast cancer (TNBC) patients. Here we investigated the mechanisms by which CD73 might contribute to TNBC progression. This was done by inhibiting CD73 with adenosine 5′-(α, β-methylene) diphosphate (APCP) in MDA-MB-231 or 4T1 TNBC cells or through shRNA-silencing (sh-CD73). Effects of such inhibition on cell behavior was then studied in normoxia and hypoxia in vitro and in an orthotopic mouse model in vivo. CD73 inhibition, through shRNA or APCP significantly decreased cellular viability and migration in normoxia. Inhibition of CD73 also resulted in suppression of hypoxia-induced increase in viability and prevented cell protrusion elongation in both normoxia and hypoxia in cancer cells. Sh-CD73 4T1 cells formed significantly smaller and less invasive 3D organoids in vitro, and significantly smaller orthotopic tumors and less lung metastases than control shRNA cells in vivo. CD73 suppression increased E-cadherin and decreased vimentin expression in vitro and in vivo, proposing maintenance of a more epithelial phenotype. In conclusion, our results suggest that CD73 may promote early steps of tumor progression, possibly through facilitating epithelial–mesenchymal transition.

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