Publications by authors named "Katarzyna Pogoda"

58 Publications

High expression of progesterone receptor may be an adverse prognostic factor in oestrogen receptor-negative/progesterone receptor-positive breast cancer: results of comprehensive re-evaluation of multi-institutional case series.

Pathology 2022 Jan 21. Epub 2022 Jan 21.

Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland. Electronic address:

Oestrogen receptor (ER)-negative (-) progesterone receptor (PgR)-positive (+) is the least common combination of steroid receptor expression observed in breast cancer. There are many controversies regarding the actual existence of ER-/PgR+ phenotype. In the current study, we aimed to perform comprehensive immunohistochemical re-evaluation of ER-/PgR+ breast cancers from multiple institutions. A total of 135 cases of ER-/PgR+ breast cancer were collected from 11 institutions from the period 2006-2020 and subsequently stained with three clinically validated anti-ER antibody clones: SP1 (Roche), 1D5 (Dako), and EP1 (Dako), and two anti-PgR antibody clones: 636 (Dako), and 1E2 (Roche). Clinicopathological characteristics of confirmed and re-categorised cases were analysed. Seventy-six cases retained the original ER-/PgR+ phenotype, including 21 HER2+ and 55 HER2- tumours. Forty-seven cases were ER+ with at least one anti-ER antibody, and 12 cases were re-categorised as double-negatives across all anti-ER and anti-PgR antibodies. No significant differences in survival were observed between groups in the HER2+ category. In the HER2- cohort, confirmed ER-/PgR+, ER+ tumours with discrepant ER staining, and triple negatives had inferior overall survival compared to concordant ER+ cases. Progesterone receptor expression in >20% of cells was identified as an adverse prognostic factor in ER-/PgR+/HER2- breast cancer in a multivariable model adjusted by stage (HR 5.0, 95% CI 1.3-19.2, p=0.019). We performed one of the largest validation studies so far on ER-/PgR+ breast cancer and confirmed the existence of this subgroup. Moreover, we identified high PgR expression as an adverse prognostic factor.
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http://dx.doi.org/10.1016/j.pathol.2021.10.003DOI Listing
January 2022

Higher platelet counts correlate to tumour progression and can be induced by intratumoural stroma in non-metastatic breast carcinomas.

Br J Cancer 2021 Dec 2. Epub 2021 Dec 2.

Laboratory of Translational Oncology, Institute of Medical Biotechnology and Experimental Oncology, Medical University of Gdańsk, Gdańsk, Poland.

Background: Platelets support tumour progression. However, their prognostic significance and relation to circulating tumour cells (CTCs) in operable breast cancer (BrCa) are still scarcely known and, thus, merit further investigation.

Methods: Preoperative platelet counts (PCs) were compared with clinical data, CTCs, 65 serum cytokines and 770 immune-related transcripts obtained using the NanoString technology.

Results: High normal PC (hPC; defined by the 75th centile cut-off) correlated with an increased number of lymph node metastases and mesenchymal CTCs in the 70 operable BrCa patients. Patients with hPC and CTC presence revealed the shortest overall survival compared to those with no CTC/any PC or even CTC/normal PC. Adverse prognostic impact of hPC was observed only in the luminal subtype, when 247 BrCa patients were analysed. hPC correlated with high content of intratumoural stroma, specifically its phenotype related to CD8+ T and resting mast cells, and an increased concentration of cytokines related to platelet activation or even production in bone marrow (i.e. APRIL, ENA78/CXCL5, HGF, IL16, IL17a, MDC/CCL22, MCP3, MMP1 and SCF).

Conclusions: Preoperative platelets evaluated alone and in combination with CTCs have prognostic potential in non-metastatic BrCa and define patients at the highest risk of disease progression, putatively benefiting from anti-platelet therapy.
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http://dx.doi.org/10.1038/s41416-021-01647-9DOI Listing
December 2021

A Novel Method to Make Polyacrylamide Gels with Mechanical Properties Resembling those of Biological Tissues.

Bio Protoc 2021 Aug 20;11(16):e4131. Epub 2021 Aug 20.

Department of Physiology, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA.

Studies characterizing how cells respond to the mechanical properties of their environment have been enabled by the use of soft elastomers and hydrogels as substrates for cell culture. A limitation of most such substrates is that, although their elastic properties can be accurately controlled, their viscous properties cannot, and cells respond to both elasticity and viscosity in the extracellular material to which they bind. Some approaches to endow soft substrates with viscosity as well as elasticity are based on coupling static and dynamic crosslinks in series within polymer networks or forming gels with a combination of sparse chemical crosslinks and steric entanglements. These materials form viscoelastic fluids that have revealed significant effects of viscous dissipation on cell function; however, they do not completely capture the mechanical features of soft solid tissues. In this report, we describe a method to make viscoelastic solids that more closely mimic some soft tissues using a combination of crosslinked networks and entrapped linear polymers. Both the elastic and viscous moduli of these substrates can be altered separately, and methods to attach cells to either the elastic or the viscous part of the network are described. Graphic abstract: Polyacrylamide gels with independently controlled elasticity and viscosity.
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http://dx.doi.org/10.21769/BioProtoc.4131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413537PMC
August 2021

The Atr-Chek1 pathway inhibits axon regeneration in response to Piezo-dependent mechanosensation.

Nat Commun 2021 06 22;12(1):3845. Epub 2021 Jun 22.

Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Atr is a serine/threonine kinase, known to sense single-stranded DNA breaks and activate the DNA damage checkpoint by phosphorylating Chek1, which inhibits Cdc25, causing cell cycle arrest. This pathway has not been implicated in neuroregeneration. We show that in Drosophila sensory neurons removing Atr or Chek1, or overexpressing Cdc25 promotes regeneration, whereas Atr or Chek1 overexpression, or Cdc25 knockdown impedes regeneration. Inhibiting the Atr-associated checkpoint complex in neurons promotes regeneration and improves synapse/behavioral recovery after CNS injury. Independent of DNA damage, Atr responds to the mechanical stimulus elicited during regeneration, via the mechanosensitive ion channel Piezo and its downstream NO signaling. Sensory neuron-specific knockout of Atr in adult mice, or pharmacological inhibition of Atr-Chek1 in mammalian neurons in vitro and in flies in vivo enhances regeneration. Our findings reveal the Piezo-Atr-Chek1-Cdc25 axis as an evolutionarily conserved inhibitory mechanism for regeneration, and identify potential therapeutic targets for treating nervous system trauma.
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http://dx.doi.org/10.1038/s41467-021-24131-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219705PMC
June 2021

Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment.

Elife 2021 06 9;10. Epub 2021 Jun 9.

Institut Cochin, INSERM U1016/CNRS UMR 8104, Université de Paris, Paris, France.

Only a fraction of cancer patients benefits from immune checkpoint inhibitors. This may be partly due to the dense extracellular matrix (ECM) that forms a barrier for T cells. Comparing five preclinical mouse tumor models with heterogeneous tumor microenvironments, we aimed to relate the rate of tumor stiffening with the remodeling of ECM architecture and to determine how these features affect intratumoral T cell migration. An ECM-targeted strategy, based on the inhibition of lysyl oxidase, was used. In vivo stiffness measurements were found to be strongly correlated with tumor growth and ECM crosslinking but negatively correlated with T cell migration. Interfering with collagen stabilization reduces ECM content and tumor stiffness leading to improved T cell migration and increased efficacy of anti-PD-1 blockade. This study highlights the rationale of mechanical characterizations in solid tumors to understand resistance to immunotherapy and of combining treatment strategies targeting the ECM with anti-PD-1 therapy.
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http://dx.doi.org/10.7554/eLife.58688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203293PMC
June 2021

Inhomogeneity of stiffness and density of the extracellular matrix within the leukoplakia of human oral mucosa as potential physicochemical factors leading to carcinogenesis.

Transl Oncol 2021 Jul 1;14(7):101105. Epub 2021 May 1.

Institute of Nuclear Physics Polish Academy of Sciences, PL-31342 Krakow, Poland; Department of Microbiology and Immunology, Institute of Medical Science, Collegium Medicum, Jan Kochanowski University in Kielce, PL-25317 Kielce, Poland. Electronic address:

Oral leukoplakia is a clinical term relating to various morphological lesions, including squamous cell hyperplasia, dysplasia and carcinoma. Leukoplakia morphologically manifested as hyperplasia with epithelial dysplasia is clinically treated as precancerous condition. Nevertheless, there is a lack of good markers indicating the transformation of premalignancies towards cancer. A better understanding of the mechanical environment within the tissues where tumors grow might be beneficial for the development of prevention, diagnostic, and treatment methods in cancer management. Atomic force microscopy (AFM) and immunohistology techniques were used to assess changes in the stiffness and morphology of oral mucosa and leukoplakia samples at different stages of their progression towards cancer. The Young's moduli of the tested leukoplakia samples were significantly higher than those of the surrounding mucus. Robust inhomogeneity of stiffness within leukoplakia samples, reflecting an increase in regeneration and collagen accumulation (increasing density) in the extracellular matrix (ECM), was observed. Within the histologically confirmed cancer samples, Young's moduli were significantly lower than those within the precancerous ones. Inhomogeneous stiffness within leukoplakia might act as "a mechanoagonist" that promotes oncogenesis. In contrast, cancer growth might require the reorganization of tissue structure to create a microenvironment with lower and homogenous stiffness. The immunohistology data collected here indicates that changes in tissue stiffness are achieved by increasing cell/ECM density. The recognition of new markers of premalignancy will aid in the development of new therapies and will expand the diagnostic methods.
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http://dx.doi.org/10.1016/j.tranon.2021.101105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111093PMC
July 2021

The Impact of Preprocessing Methods for a Successful Prostate Cell Lines Discrimination Using Partial Least Squares Regression and Discriminant Analysis Based on Fourier Transform Infrared Imaging.

Cells 2021 04 20;10(4). Epub 2021 Apr 20.

Institute of Nuclear Physics Polish Academy of Sciences, PL-31342 Krakow, Poland.

Fourier transform infrared spectroscopy (FT-IR) is widely used in the analysis of the chemical composition of biological materials and has the potential to reveal new aspects of the molecular basis of diseases, including different types of cancer. The potential of FT-IR in cancer research lies in its capability of monitoring the biochemical status of cells, which undergo malignant transformation and further examination of spectral features that differentiate normal and cancerous ones using proper mathematical approaches. Such examination can be performed with the use of chemometric tools, such as partial least squares discriminant analysis (PLS-DA) classification and partial least squares regression (PLSR), and proper application of preprocessing methods and their correct sequence is crucial for success. Here, we performed a comparison of several state-of-the-art methods commonly used in infrared biospectroscopy (denoising, baseline correction, and normalization) with the addition of methods not previously used in infrared biospectroscopy classification problems: Mie extinction extended multiplicative signal correction, Eiler's smoothing, and probabilistic quotient normalization. We compared all of these approaches and their effect on the data structure, classification, and regression capability on experimental FT-IR spectra collected from five different prostate normal and cancerous cell lines. Additionally, we tested the influence of added spectral noise. Overall, we concluded that in the case of the data analyzed here, the biggest impact on data structure and performance of PLS-DA and PLSR was caused by the baseline correction; therefore, much attention should be given, especially to this step of data preprocessing.
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http://dx.doi.org/10.3390/cells10040953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073124PMC
April 2021

Dynamic Tuning of Viscoelastic Hydrogels with Carbonyl Iron Microparticles Reveals the Rapid Response of Cells to Three-Dimensional Substrate Mechanics.

ACS Appl Mater Interfaces 2021 May 28;13(18):20947-20959. Epub 2021 Apr 28.

Department of Biomedical Engineering, Rowan University, Glassboro, New Jersey 08028, United States.

Current methods to dynamically tune three-dimensional hydrogel mechanics require specific chemistries and substrates that make modest, slow, and often irreversible changes in their mechanical properties, exclude the use of protein-based scaffolds, or alter the hydrogel microstructure and pore size. Here, we rapidly and reversibly alter the mechanical properties of hydrogels consisting of extracellular matrix proteins and proteoglycans by adding carbonyl iron microparticles (MPs) and applying external magnetic fields. This approach drastically alters hydrogel mechanics: rheology reveals that application of a 4000 Oe magnetic field to a 5 mg/mL collagen hydrogel containing 10 wt % MPs increases the storage modulus from approximately 1.5 to 30 kPa. Cell morphology experiments show that cells embedded within these hydrogels rapidly sense the magnetically induced changes in ECM stiffness. Ca transients are altered within seconds of stiffening or subsequent softening, and slower but still dynamic changes occur in YAP nuclear translocation in response to time-dependent application of a magnetic field. The near instantaneous change in hydrogel mechanics provides new insight into the effect of changing extracellular stiffness on both acute and chronic changes in diverse cell types embedded in protein-based scaffolds. Due to its flexibility, this method is broadly applicable to future studies interrogating cell mechanotransduction in three-dimensional substrates.
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http://dx.doi.org/10.1021/acsami.0c21868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317442PMC
May 2021

Pyoderma Gangrenosum with an Underlying Leukocyte Adhesion Deficiency Type 1 (LAD-1) and Pregnancy in the Shade of COVID-19 Epidemic: A Patient and Physician Experience.

Dermatol Ther (Heidelb) 2021 Jun 8;11(3):643-653. Epub 2021 Mar 8.

Department of Dermatology, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszów, Poland.

In the first part of this article, the anonymous patient diagnosed with leukocyte adhesion deficiency type 1 (LAD-1) and pyoderma gangrenosum (PG) discusses her experience of her medical history and treatment in a foreign country during her pregnancy and the coronavirus disease-19 (COVID-19) pandemic. The patient's dermatologists, immunologist, and diagnostician refer to the epidemiology, genetics, diagnosis, morphologic manifestations, including skin lesions, treatment, and prognosis in LAD-1. The patient's diagnostic and therapeutic process was discussed in the last part of this paper.
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http://dx.doi.org/10.1007/s13555-021-00507-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939102PMC
June 2021

Clinical behavior and outcomes of breast cancer in young women with germline BRCA pathogenic variants.

NPJ Breast Cancer 2021 Feb 12;7(1):16. Epub 2021 Feb 12.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Young breast cancer (BC) patients carrying a germline BRCA pathogenic variant (mBRCA) have similar outcomes as non-carriers. However, the impact of the type of gene (BRCA1 vs. BRCA2) and hormone receptor status (positive [HR+] vs. negative [HR-]) on clinical behavior and outcomes of mBRCA BC remains largely unknown. This is an international, multicenter, hospital-based, retrospective cohort study that included mBRCA patients diagnosed, between January 2000 and December 2012, with stage I-III invasive early BC at age ≤40 years. From 30 centers worldwide, 1236 young mBRCA BC patients were included. Among 808 and 428 patients with mBRCA1 or mBRCA2, 191 (23.6%) and 356 (83.2%) had HR+tumors, respectively (P < 0.001). Median follow-up was 7.9 years. Second primary BC (P = 0.009) and non-BC malignancies (P = 0.02) were more frequent among mBRCA1 patients while distant recurrences were less frequent (P = 0.02). Irrespective of hormone receptor status, mBRCA1 patients had worse disease-free survival (DFS; adjusted HR = 0.76, 95% CI = 0.60-0.96), with no difference in distant recurrence-free interval (DRFI) and overall survival (OS). Patients with HR+ disease had more frequent distant recurrences (P < 0.001) and less frequent second primary malignancies (BC: P = 0.005; non-BC: P = 0.18). No differences in DFS and OS were observed according to hormone receptor status, with a tendency for worse DRFI (adjusted HR = 1.39, 95% CI = 0.94-2.05) in patients with HR+ BC. Type of mBRCA gene and hormone receptor status strongly impact BC clinical behavior and outcomes in mBRCA young patients. These results provide important information for patients' counseling on treatment, prevention, and surveillance strategies.
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http://dx.doi.org/10.1038/s41523-021-00224-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880991PMC
February 2021

In search of the correlation between nanomechanical and biomolecular properties of prostate cancer cells with different metastatic potential.

Arch Biochem Biophys 2021 01 6;697:108718. Epub 2020 Dec 6.

Institute of Nuclear Physics Polish Academy of Sciences, Krakow, PL-31342, Poland.

Nanomechanical properties of living cells, as measured with atomic force microscopy (AFM), are increasingly recognized as criteria that differentiate normal and pathologically altered cells. Locally measured cell elastic properties, described by the parameter known as Young's modulus, are currently proposed as a new diagnostic parameter that can be used at the early stage of cancer detection. In this study, local mechanical properties of normal human prostate (RWPE-1) cells and a range of malignant (22Rv1) and metastatic prostate cells (LNCaP, Du145 and PC3) were investigated. It was found that non-malignant prostate cells are stiffer than cancer cells while the metastatic cells are much softer than malignant cells from the primary tumor site. Next, the biochemical properties of the cells were measured using confocal Raman (RS) and Fourier-transform infrared (FT-IR) spectroscopies to reveal these cells' biochemical composition as malignant transformation proceeds. Nanomechanical and biochemical profiles of five different prostate cell lines were subsequently analyzed using partial least squares regression (PLSR) in order to identify which spectral features of the RS and FT-IR spectra correlate with the cell's elastic properties. The PLSR-based model could predict Young's modulus values based on both RS and FT-IR spectral information. These outcomes show not only that AFM, RS and FT-IR techniques can be used for discrimination between normal and cancer cells, but also that a linear correlation between mechanical response and biomolecular composition of the cells that undergo malignant transformation can be found. This knowledge broadens our understanding of how prostate cancer cells evolve thorough the multistep process of tumor pathogenesis.
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http://dx.doi.org/10.1016/j.abb.2020.108718DOI Listing
January 2021

Physics Comes to the Aid of Medicine-Clinically-Relevant Microorganisms through the Eyes of Atomic Force Microscope.

Pathogens 2020 Nov 20;9(11). Epub 2020 Nov 20.

Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Bialystok, PL-15222 Bialystok, Poland.

Despite the hope that was raised with the implementation of antibiotics to the treatment of infections in medical practice, the initial enthusiasm has substantially faded due to increasing drug resistance in pathogenic microorganisms. Therefore, there is a need for novel analytical and diagnostic methods in order to extend our knowledge regarding the mode of action of the conventional and novel antimicrobial agents from a perspective of single microbial cells as well as their communities growing in infected sites, i.e., biofilms. In recent years, atomic force microscopy (AFM) has been mostly used to study different aspects of the pathophysiology of noninfectious conditions with attempts to characterize morphological and rheological properties of tissues, individual mammalian cells as well as their organelles and extracellular matrix, and cells' mechanical changes upon exposure to different stimuli. At the same time, an ever-growing number of studies have demonstrated AFM as a valuable approach in studying microorganisms in regard to changes in their morphology and nanomechanical properties, e.g., stiffness in response to antimicrobial treatment or interaction with a substrate as well as the mechanisms behind their virulence. This review summarizes recent developments and the authors' point of view on AFM-based evaluation of microorganisms' response to applied antimicrobial treatment within a group of selected bacteria, fungi, and viruses. The AFM potential in development of modern diagnostic and therapeutic methods for combating of infections caused by drug-resistant bacterial strains is also discussed.
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http://dx.doi.org/10.3390/pathogens9110969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699805PMC
November 2020

Nanomechanics and Histopathology as Diagnostic Tools to Characterize Freshly Removed Human Brain Tumors.

Int J Nanomedicine 2020 6;15:7509-7521. Epub 2020 Oct 6.

Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Bialystok, Bialystok PL-15222, Poland.

Background: The tissue-mechanics environment plays a crucial role in human brain physiological development and the pathogenesis of different diseases, especially cancer. Assessment of alterations in brain mechanical  properties during cancer progression might provide important information about possible tissue abnormalities with clinical relevance.

Methods: With atomic force microscopy (AFM), the stiffness of freshly removed human brain tumor tissue was determined on various regions of the sample and compared to the stiffness of healthy human brain tissue that was removed during neurosurgery to gain access to tumor mass. An advantage of indentation measurement using AFM is the small volume of tissue required and high resolution at the single-cell level.

Results: Our results showed great heterogeneity of stiffness within metastatic cancer or primary high-grade gliomas compared to healthy tissue. That effect was not clearly visible in lower-grade tumors like meningioma.

Conclusion: Collected data indicate that AFM might serve as a diagnostic tool in the assessment of human brain tissue stiffness in the process of recognizing tumors.
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http://dx.doi.org/10.2147/IJN.S270147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547774PMC
November 2020

Tissue Rheology as a Possible Complementary Procedure to Advance Histological Diagnosis of Colon Cancer.

ACS Biomater Sci Eng 2020 10 7;6(10):5620-5631. Epub 2020 Sep 7.

Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Bialystok, 15-222 Bialystok, Poland.

In recent years, rheological measurements of cells and tissues at physiological and pathological stages have become an essential method to determine how forces and changes in mechanical properties contribute to disease development and progression, but there is no standardization of this procedure so far. In this study, we evaluate the potential of nanoscale atomic force microscopy (AFM) and macroscopic shear rheometry to assess the mechanical properties of healthy and cancerous human colon tissues. The direct comparison of tissue mechanical behavior under uniaxial and shear deformation shows that cancerous tissues not only are stiffer compared to healthy tissue but also respond differently when shear and compressive stresses are applied. These results suggest that rheological parameters can be useful measures of colon cancer mechanopathology. Additionally, we extend the list of biological materials exhibiting compressional stiffening and shear weakening effects to human colon tumors. These mechanical responses might be promising mechanomarkers and become part of the new procedures in colon cancer diagnosis. Enrichment of histopathological grading with rheological assessment of tissue mechanical properties will potentially allow more accurate colon cancer diagnosis and improve prognosis.
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http://dx.doi.org/10.1021/acsbiomaterials.0c00975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549092PMC
October 2020

microRNA Expression Profile in Single Hormone Receptor-Positive Breast Cancers is Mainly Dependent on HER2 Status-A Pilot Study.

Diagnostics (Basel) 2020 Aug 20;10(9). Epub 2020 Aug 20.

Department of Oncology and Radiotherapy, Medical University of Gdansk, 80-214 Gdansk, Poland.

Estrogen (ER) and progesterone (PgR) receptors and HER2 are crucial in the assessment of breast cancer specimens due to their prognostic and predictive significance. Single hormone receptor-positive breast cancers are less common and their clinical course is less favorable than ER(+)/PgR(+) tumors. Their molecular features, especially microRNA (miRNA) profiles, have not been investigated to date. Tumor specimens from 36 chemonaive breast cancer patients with known ER and PgR status (18 ER(+)/PgR(-) and 18 ER(-)/PgR(+) cases) were enrolled to the study. The expression of 829 miRNAs was evaluated with nCounter Human v3 miRNA expression Assay (NanoString). miRNAs differentiating between ER/PgR/HER2 phenotypes were selected based on fold change (FC) calculated for the mean normalized counts of each probe in compared groups. The differences were estimated with Student's -test or Two-Way ANOVA (considering also the HER2 status). The results were validated using The Cancer Genome Atlas (TCGA) dataset. Following quality control of raw data, fourcases were excluded due to low sample quality, leaving 14 ER(+)/PgR(-) and 18 ER(-)/PgR(+) cases. After correction for multiple comparisons, we did not find miRNA signature differentiating between ER(-)/PgR(+) and ER(+)/PgR(-) breast cancers. However, a trend for differing expression (-value ≤ 0.05; FDR > 0.2; ANOVA) in eight miRNAs was observed. The ER(+)/PgR(-) group demonstrated elevated levels of four miRNAs-miR-30a-5p, miR-29c-3p, miR-141-3p and miR-423-5p-while the ER(-)/PgR(+) tumors were enriched in another four miRNAs-miR-514b-5p, miR-424-5p, miR-495-3p, and miR-92a-3p. For one of the miRNAs-miR-29c-3p-the association with the ER(+)/PgR(-) phenotype was confirmed in the TCGA cohort (-value = 0.024; -test). HER2 amplification/overexpression in the NanoString cohort was related to significant differences observed in 33 miRNA expression levels (FDR ≤ 0.2; ANOVA). The association with HER2 status was confirmed in the TCGA cohort for four miRNAs (miR-1180-3p, miR-223-3p, miR-30d-5p, and miR-195-5p). The main differences in miRNA expression amongst single hormone receptor-positive tumors were identified according to their HER2 status. However, ER(+)/PgR(-) cases tended to express higher levels of miRNAs associated with ER-positivity (miR-30a-5p, miR-29c-3p, miR-141-3p), whereas ER(-)/PgR(+) cancers showed elevated levels of miRNAs characteristic for double- and triple-negative tumors (miR-92a-3p, miR-424-5p). Further studies are necessary to comprehensively analyze miRNA signatures characteristic of ER(-)/PgR(+) and ER(+)/PgR(-) tumors.
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http://dx.doi.org/10.3390/diagnostics10090617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555149PMC
August 2020

Indenting soft samples (hydrogels and cells) with cantilevers possessing various shapes of probing tip.

Eur Biophys J 2020 Sep 17;49(6):485-495. Epub 2020 Aug 17.

Institute of Nuclear Physics Polish Academy of Sciences, PL-31342, Kraków, Poland.

The identification of cancer-related changes in cells and tissues based on the measurements of elastic properties using atomic force microscopy (AFM) seems to be approaching clinical application. Several limiting aspects have already been discussed; however, still, no data have shown how specific AFM probe geometries are related to the biomechanical evaluation of cancer cells. Here, we analyze and compare the nanomechanical results of mechanically homogenous polyacrylamide gels and heterogeneous bladder cancer cells measured using AFM probes of various tip geometry, including symmetric and non-symmetric pyramids and a sphere. Our observations show large modulus variability aligned with both types of AFM probes used and with the internal structure of the cells. Altogether, these results demonstrate that it is possible to differentiate between compliant and rigid samples of kPa elasticity; however, simultaneously, they highlight the strong need for standardized protocols for AFM-based elasticity measurements if applied in clinical practice including the use of a single type of AFM cantilever.
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http://dx.doi.org/10.1007/s00249-020-01456-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456413PMC
September 2020

Elasticity-dependent response of malignant cells to viscous dissipation.

Biomech Model Mechanobiol 2021 Feb 12;20(1):145-154. Epub 2020 Aug 12.

Institute for Medicine and Engineering and Center for Engineering MechanoBiology, University of Pennsylvania, Philadelphia, PA, USA.

The stiffness of the cellular environment controls malignant cell phenotype and proliferation. However, the effect of viscous dissipation on these parameters has not yet been investigated, in part due to the lack of in vitro cell substrates reproducing the mechanical properties of normal tissues and tumors. In this article, we use a newly reported viscoelastic polyacrylamide gel cell substrate, and we characterize the impact of viscous dissipation on three malignant cell lines: DU145 and PC3 derived from prostate and LN229 from brain. The spreading, motility and proliferation rates of these cells were analyzed on 1 kPa and 5 kPa elastic and viscoelastic gels. Surprisingly, the effect of substrate viscous dissipation on cell behavior depended on substrate stiffness for the three cell types tested. We conclude that viscoelasticity controls the spreading, proliferation and migration of malignant cells in vitro. These results highlight the critical role of viscous dissipation in the phenotype and proliferation of malignant cells, especially in stiff tumor environments.
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http://dx.doi.org/10.1007/s10237-020-01374-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892690PMC
February 2021

Pregnancy After Breast Cancer in Patients With Germline Mutations.

J Clin Oncol 2020 09 16;38(26):3012-3023. Epub 2020 Jul 16.

Department of Medical Oncology, Institut Jules Bordet and Université Libre de, Brussels, Belgium.

Purpose: Young women with germline mutations have unique reproductive challenges. Pregnancy after breast cancer does not increase the risk of recurrence; however, very limited data are available in patients with mutations. This study investigated the impact of pregnancy on breast cancer outcomes in patients with germline mutations.

Patients And Methods: This is an international, multicenter, hospital-based, retrospective cohort study. Eligible patients were diagnosed between January 2000 and December 2012 with invasive early breast cancer at age ≤ 40 years and harbored deleterious germline mutations. Primary end points were pregnancy rate, and disease-free survival (DFS) between patients with and without a pregnancy after breast cancer. Pregnancy outcomes and overall survival (OS) were secondary end points. Survival analyses were adjusted for guarantee-time bias controlling for known prognostic factors.

Results: Of 1,252 patients with germline mutations (, 811 patients; , 430 patients; , 11 patients) included, 195 had at least 1 pregnancy after breast cancer (pregnancy rate at 10 years, 19%; 95% CI, 17% to 22%). Induced abortions and miscarriages occurred in 16 (8.2%) and 20 (10.3%) patients, respectively. Among the 150 patients who gave birth (76.9%; 170 babies), pregnancy complications and congenital anomalies occurred in 13 (11.6%) and 2 (1.8%) cases, respectively. Median follow-up from breast cancer diagnosis was 8.3 years. No differences in DFS (adjusted hazard ratio [HR], 0.87; 95% CI, 0.61 to 1.23; = .41) or OS (adjusted HR, 0.88; 95% CI, 0.50 to 1.56; = .66) were observed between the pregnancy and nonpregnancy cohorts.

Conclusion: Pregnancy after breast cancer in patients with germline mutations is safe without apparent worsening of maternal prognosis and is associated with favorable fetal outcomes. These results provide reassurance to patients with -mutated breast cancer interested in future fertility.
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http://dx.doi.org/10.1200/JCO.19.02399DOI Listing
September 2020

A novel method to make viscoelastic polyacrylamide gels for cell culture and traction force microscopy.

APL Bioeng 2020 Sep 2;4(3):036104. Epub 2020 Jul 2.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.

Polyacrylamide hydrogels are commonly used in cell biology, notably to cultivate cells on soft surfaces. Polyacrylamide gels are purely elastic and well adapted to cell culture as they are inert and can be conjugated with adhesion proteins. Here, we report a method to make viscoelastic polyacrylamide gels with mechanical properties more closely resembling biological tissues and suitable for cell culture . We demonstrate that these gels can be used for traction force microscopy experiments. We also show that multiple cell types respond to the viscoelasticity of their substrate and that viscous dissipation has an influence on cell spreading, contractility, and motility. This new material provides new opportunities for investigating how normal or malignant cells sense and respond to viscous dissipation within the extra-cellular matrix.
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http://dx.doi.org/10.1063/5.0002750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334032PMC
September 2020

Limitations of Systemic Oncological Therapy in Breast Cancer Patients with Chronic Kidney Disease.

J Oncol 2020 18;2020:7267083. Epub 2020 May 18.

Department of Internal Diseases and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice 40-027, Poland.

Breast cancer is the most common malignancy, affecting middle-age and older women frequently suffering from other chronic diseases, including chronic kidney disease. The risk of breast cancer development in women on renal replacement therapy (peritoneal dialysis and haemodialysis) is higher than in the general population. Chronic kidney disease does not limit surgical treatment or radiotherapy; however, it affects the pharmacokinetics of drugs used in the systematic treatment to a different extent, increasing their toxicity and the risk of adverse drug reactions. This article summarizes the current knowledge (published studies accessed through PUBMED) on drugs used in chemotherapy, hormone therapy, anti-HER2 drugs, CDK4/6 inhibitors, PARP inhibitors, and immune therapy in breast cancer patients undergoing dialysis. We discuss the data, the optimal choice of the chemotherapeutic protocol, and the administration of drugs in a specific time relation to the haemodialysis session to ensure the most effective and safe treatment to breast cancer patients.
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http://dx.doi.org/10.1155/2020/7267083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251456PMC
May 2020

Minimally Important Differences for Interpreting EORTC QLQ-C30 Scores in Patients With Advanced Breast Cancer.

JNCI Cancer Spectr 2019 Sep 4;3(3):pkz037. Epub 2019 Jun 4.

European Organisation for Research and Treatment of Cancer, Brussels, Belgium.

Background: We aimed to estimate the minimally important difference (MID) for interpreting group-level change over time, both within a group and between groups, for the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (EORTC QLQ-C30) scores in patients with advanced breast cancer.

Methods: Data were derived from two published EORTC trials. Clinical anchors (eg, performance status [PS]) were selected using correlation strength and clinical plausibility of their association with a particular QLQ-C30 scale. Three change status groups were formed: deteriorated by one anchor category, improved by one anchor category, and no change. Patients with greater anchor changes were excluded. The mean change method was used to estimate MIDs for within-group change, and linear regression was used to estimate MIDs for between-group differences in change over time. For a given QLQ-C30 scale, MID estimates from multiple anchors were triangulated to a single value via a correlation-based weighted average.

Results: MIDs varied by QLQ-C30 scale, direction (improvement vs deterioration), and anchor. MIDs for within-group change ranged from 5 to 14 points (improvement) and -14 to -4 points (deterioration), and MIDs for between-group change over time ranged from 4 to 11 points and from -18 to -4 points. Correlation-weighted MIDs for most QLQ-C30 scales ranged from 4 to 10 points in absolute values.

Conclusions: Our findings aid interpretation of changes in EORTC QLQ-C30 scores over time, both within and between groups, and for performing more accurate sample size calculations for clinical trials in advanced breast cancer.
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http://dx.doi.org/10.1093/jncics/pkz037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050000PMC
September 2019

Effects of Germline Mutations on Triple-Negative Breast Cancer Prognosis.

J Oncol 2020 27;2020:8545643. Epub 2020 Jan 27.

Department of Breast Cancer and Reconstructive Surgery, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland.

Germline and mutations confer an increased lifetime risk for breast cancer and ovarian cancer. Several studies have investigated prognosis among mutation carriers and noncarriers, but the prognostic impact on outcomes of breast cancer patients has not been determined. The aim of this study was to determine the prognosis of TNBC patients with and without germline mutation. Among 502 patients diagnosed with TNBC between 2005 and 2008, 124 patients with a strong family history of breast cancer or ovarian cancer as well as TNBC patients diagnosed under 45 years were referred to the Genetic Counseling Unit for genetic counselling and genetic tests. In 30 (24%) of them, the mutation was detected (the most common 5382insC in 18 (60%) patients). The median follow-up of the entire group was 60 months. mutation carriers were statistically significantly younger at TNBC diagnosis compared with nonmutation patients (41 vs 47 years, respectively). Patients with the mutation had smaller tumors (stage I: 47% vs 24.5% in noncarriers), but there was no significant difference in the regional nodal status (58.5-63% with cN0). Contralateral breast cancer developed in 26.5% of mutation carriers and in 14% of noncarriers. Other primary cancers were also slightly more common in mutation carriers (16.5% vs 9.5%). The performed analysis did not show any significant differences between the groups in recurrence-free survival (=0.312). There was no significant difference between patients with or without mutation as regards overall survival (=0.649) and the risk of TNBC death (=0.333). The survival from detection of metastases was similar in two groups (=0.865). Our study demonstrated that the mutation does not affect TNBC patients' outcomes.
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http://dx.doi.org/10.1155/2020/8545643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165358PMC
January 2020

Loops versus lines and the compression stiffening of cells.

Soft Matter 2020 May 6;16(18):4389-4406. Epub 2020 Apr 6.

Physics Department, Syracuse University, Syracuse, NY 13244, USA.

Both animal and plant tissue exhibit a nonlinear rheological phenomenon known as compression stiffening, or an increase in moduli with increasing uniaxial compressive strain. Does such a phenomenon exist in single cells, which are the building blocks of tissues? One expects an individual cell to compression soften since the semiflexible biopolymer-based cytoskeletal network maintains the mechanical integrity of the cell and in vitro semiflexible biopolymer networks typically compression soften. To the contrary, we find that mouse embryonic fibroblasts (mEFs) compression stiffen under uniaxial compression via atomic force microscopy studies. To understand this finding, we uncover several potential mechanisms for compression stiffening. First, we study a single semiflexible polymer loop modeling the actomyosin cortex enclosing a viscous medium modeled as an incompressible fluid. Second, we study a two-dimensional semiflexible polymer/fiber network interspersed with area-conserving loops, which are a proxy for vesicles and fluid-based organelles. Third, we study two-dimensional fiber networks with angular-constraining crosslinks, i.e. semiflexible loops on the mesh scale. In the latter two cases, the loops act as geometric constraints on the fiber network to help stiffen it via increased angular interactions. We find that the single semiflexible polymer loop model agrees well with the experimental cell compression stiffening finding until approximately 35% compressive strain after which bulk fiber network effects may contribute. We also find for the fiber network with area-conserving loops model that the stress-strain curves are sensitive to the packing fraction and size distribution of the area-conserving loops, thereby creating a mechanical fingerprint across different cell types. Finally, we make comparisons between this model and experiments on fibrin networks interlaced with beads as well as discuss implications for single cell compression stiffening at the tissue scale.
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http://dx.doi.org/10.1039/c9sm01627aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225031PMC
May 2020

Reference values for the EORTC QLQ-C30 in early and metastatic breast cancer.

Eur J Cancer 2020 01 12;125:69-82. Epub 2019 Dec 12.

Department of Quality of Life, European Organization of Research and Treatment for Cancer, Brussels, Belgium. Electronic address:

Background: Considering the worldwide incidence of breast cancer (BC) and the importance of health-related quality of life (HRQoL) assessment, there is a growing need to have accurate and up-to-date reference values (RVs). RVs are useful for the design of randomised controlled trials (RCTs) and as benchmarks for comparison of cancer RCTs and health care interventions. This study aimed to provide RVs for the QLQ-C30 in early BC (EBC) and metastatic BC (MBC). General patterns of main results from the EORTC dataset (main dataset) were compared with the PDS dataset (comparison dataset) to see whether they would be consistent across pre-defined covariates.

Methods: European Organization for Research and Treatment of Cancer (EORTC) (main dataset) and Project Data Sphere (PDS) (comparison dataset) were searched to identify BC RCTs where baseline HRQoL (before treatment) was assessed with the QLQ-C30. RVs were calculated and stratified by disease stage, age, and when available, performance status (PS), comorbidity and region. RVs were reported using descriptive statistics.

Results: Data from three EORTC (n = 4115) and three PDS RCTs (n = 1406) were included in the analysis. While EBC patients presented better HRQoL with high baseline functioning scores and low prevalence of symptoms, MBC patients reported worse HRQoL with lower functioning scores and more prevalence of symptoms. In MBC, poor PS and presence of comorbidities reflected worse baseline HRQoL. No consistent differences were found for age and countries.

Conclusion: These up-to-date RVs for the EORTC QLQ-C30 in BC show differences in HRQoL scores between stages, PS, and comorbidities. These findings, supported by an independent dataset, will help the clinical interpretation of scores for BCpatients.
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http://dx.doi.org/10.1016/j.ejca.2019.10.031DOI Listing
January 2020

Loss of Vimentin Enhances Cell Motility through Small Confining Spaces.

Small 2019 12 13;15(50):e1903180. Epub 2019 Nov 13.

Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, 19104, USA.

The migration of cells through constricting spaces or along fibrous tracks in tissues is important for many biological processes and depends on the mechanical properties of a cytoskeleton made up of three different filaments: F-actin, microtubules, and intermediate filaments. The signaling pathways and cytoskeletal structures that control cell motility on 2D are often very different from those that control motility in 3D. Previous studies have shown that intermediate filaments can promote actin-driven protrusions at the cell edge, but have little effect on overall motility of cells on flat surfaces. They are however important for cells to maintain resistance to repeated compressive stresses that are expected to occur in vivo. Using mouse embryonic fibroblasts derived from wild-type and vimentin-null mice, it is found that loss of vimentin increases motility in 3D microchannels even though on flat surfaces it has the opposite effect. Atomic force microscopy and traction force microscopy experiments reveal that vimentin enhances perinuclear cell stiffness while maintaining the same level of acto-myosin contractility in cells. A minimal model in which a perinuclear vimentin cage constricts along with the nucleus during motility through confining spaces, providing mechanical resistance against large strains that could damage the structural integrity of cells, is proposed.
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http://dx.doi.org/10.1002/smll.201903180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910987PMC
December 2019

Vimentin protects cells against nuclear rupture and DNA damage during migration.

J Cell Biol 2019 12 1;218(12):4079-4092. Epub 2019 Nov 1.

Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA

Mammalian cells frequently migrate through tight spaces during normal embryogenesis, wound healing, diapedesis, or in pathological situations such as metastasis. Nuclear size and shape are important factors in regulating the mechanical properties of cells during their migration through such tight spaces. At the onset of migratory behavior, cells often initiate the expression of vimentin, an intermediate filament protein that polymerizes into networks extending from a juxtanuclear cage to the cell periphery. However, the role of vimentin intermediate filaments (VIFs) in regulating nuclear shape and mechanics remains unknown. Here, we use wild-type and vimentin-null mouse embryonic fibroblasts to show that VIFs regulate nuclear shape and perinuclear stiffness, cell motility in 3D, and the ability of cells to resist large deformations. These changes increase nuclear rupture and activation of DNA damage repair mechanisms, which are rescued by exogenous reexpression of vimentin. Our findings show that VIFs provide mechanical support to protect the nucleus and genome during migration.
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http://dx.doi.org/10.1083/jcb.201902046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891099PMC
December 2019

Role of a Kinesin Motor in Cancer Cell Mechanics.

Nano Lett 2019 11 7;19(11):7691-7702. Epub 2019 Oct 7.

Institut Curie, PSL Research University, CNRS, UMR 144 , 26 rue d'Ulm , Paris Cedex 05 75248 , France.

Molecular motors play important roles in force generation, migration, and intracellular trafficking. Changes in specific motor activities are altered in numerous diseases. KIF20A, a motor protein of the kinesin-6 family, is overexpressed in bladder cancer, and KIF20A levels correlate negatively with clinical outcomes. We report here a new role for the KIF20A kinesin motor protein in intracellular mechanics. Using optical tweezers to probe intracellular mechanics and surface AFM to probe cortical mechanics, we first confirm that bladder urothelial cells soften with an increasing cancer grade. We then show that inhibiting KIF20A makes the intracellular environment softer for both high- and low-grade bladder cancer cells. Upon inhibition of KIF20A, cortical stiffness also decreases in lower grade cells, while it surprisingly increases in higher grade malignant cells. Changes in cortical stiffness correlate with the interaction of KIF20A with myosin IIA. Moreover, KIF20A inhibition negatively regulates bladder cancer cell motility irrespective of the underlying substrate stiffness. Our results reveal a central role for a microtubule motor in cell mechanics and migration in the context of bladder cancer.
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http://dx.doi.org/10.1021/acs.nanolett.9b02592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737127PMC
November 2019

Emergence of tissue-like mechanics from fibrous networks confined by close-packed cells.

Nature 2019 09 28;573(7772):96-101. Epub 2019 Aug 28.

Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA.

The viscoelasticity of the crosslinked semiflexible polymer networks-such as the internal cytoskeleton and the extracellular matrix-that provide shape and mechanical resistance against deformation is assumed to dominate tissue mechanics. However, the mechanical responses of soft tissues and semiflexible polymer gels differ in many respects. Tissues stiffen in compression but not in extension, whereas semiflexible polymer networks soften in compression and stiffen in extension. In shear deformation, semiflexible polymer gels stiffen with increasing strain, but tissues do not. Here we use multiple experimental systems and a theoretical model to show that a combination of nonlinear polymer network elasticity and particle (cell) inclusions is essential to mimic tissue mechanics that cannot be reproduced by either biopolymer networks or colloidal particle systems alone. Tissue rheology emerges from an interplay between strain-stiffening polymer networks and volume-conserving cells within them. Polymer networks that soften in compression but stiffen in extension can be converted to materials that stiffen in compression but not in extension by including within the network either cells or inert particles to restrict the relaxation modes of the fibrous networks that surround them. Particle inclusions also suppress stiffening in shear deformation; when the particle volume fraction is low, they have little effect on the elasticity of the polymer networks. However, as the particles become more closely packed, the material switches from compression softening to compression stiffening. The emergence of an elastic response in these composite materials has implications for how tissue stiffness is altered in disease and can lead to cellular dysfunction. Additionally, the findings could be used in the design of biomaterials with physiologically relevant mechanical properties.
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http://dx.doi.org/10.1038/s41586-019-1516-5DOI Listing
September 2019

Myosin IIA suppresses glioblastoma development in a mechanically sensitive manner.

Proc Natl Acad Sci U S A 2019 07 24;116(31):15550-15559. Epub 2019 Jun 24.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Jacksonville, FL 32224;

The ability of glioblastoma to disperse through the brain contributes to its lethality, and blocking this behavior has been an appealing therapeutic approach. Although a number of proinvasive signaling pathways are active in glioblastoma, many are redundant, so targeting one can be overcome by activating another. However, these pathways converge on nonredundant components of the cytoskeleton, and we have shown that inhibiting one of these-the myosin II family of cytoskeletal motors-blocks glioblastoma invasion even with simultaneous activation of multiple upstream promigratory pathways. Myosin IIA and IIB are the most prevalent isoforms of myosin II in glioblastoma, and we now show that codeleting these myosins markedly impairs tumorigenesis and significantly prolongs survival in a rodent model of this disease. However, while targeting just myosin IIA also impairs tumor invasion, it surprisingly increases tumor proliferation in a manner that depends on environmental mechanics. On soft surfaces myosin IIA deletion enhances ERK1/2 activity, while on stiff surfaces it enhances the activity of NFκB, not only in glioblastoma but in triple-negative breast carcinoma and normal keratinocytes as well. We conclude myosin IIA suppresses tumorigenesis in at least two ways that are modulated by the mechanics of the tumor and its stroma. Our results also suggest that inhibiting tumor invasion can enhance tumor proliferation and that effective therapy requires targeting cellular components that drive both proliferation and invasion simultaneously.
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http://dx.doi.org/10.1073/pnas.1902847116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681735PMC
July 2019

Compressive tumours cause neuronal damage.

Nat Biomed Eng 2019 03;3(3):171-172

Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA.

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http://dx.doi.org/10.1038/s41551-019-0370-yDOI Listing
March 2019
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