Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice

Elkabets, Moshe; Gifford, Ann; Scheel, Christina; Nilsson, Björn; Reinhardt, Ferenc; Bray, Mark-Anthony; Carpenter, Anne E.; Jirström, Karin; Magnusson, Kristina; Ebert, Benjamin L.; Pontén, Fredrik; Weinberg, Robert A.; McAllister, Sandra S.

doi:10.1172/jci43757

Cited by 183 publications

(212 citation statements)

References 68 publications

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“…Polyacrylamide substrates were fabricated as described previously (Elkabets et al, 2011). Briefly, acrylamide solution (Bio-Rad) was mixed with N-N′-methylene-bis-acrylamide solutions (Bio-Rad) and then polymerized between a glutaraldehyde-activated glass surface and hydrophobic coverslip.…”

Section: Hydrogelsmentioning

confidence: 99%

“…Polymerized substrates were then activated for protein conjugation with the heterobifunctional crosslinker Sulfo-SANPAH at 0.5 mg/ml (Pierce Chemical) under UV exposure for 15 min. After washing with HEPES buffer, functionalizing with fibronectin or type I collagen at a nominal surface density of 2.6 µg/cm was performed (Elkabets et al, 2011). Elastic moduli were determined by atomic force microscopy.…”

Section: Hydrogelsmentioning

confidence: 99%

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Mechanical signals regulate and activate SNAIL1 protein to control the fibrogenic response of cancer-associated fibroblasts

Zhang

Grither

Hove

et al. 2016

Journal of Cell Science

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Increased deposition of collagen in extracellular matrix (ECM) leads to increased tissue stiffness and occurs in breast tumors. When present, this increases tumor invasion and metastasis. Precisely how this deposition is regulated and maintained in tumors is unclear. Much has been learnt about mechanical signal transduction in cells, but transcriptional responses and the pathophysiological consequences are just becoming appreciated. Here, we show that the SNAIL1 (also known as SNAI1) protein level increases and accumulates in nuclei of breast tumor cells and cancer-associated fibroblasts (CAFs) following exposure to stiff ECM in culture and in vivo. SNAIL1 is required for the fibrogenic response of CAFs when exposed to a stiff matrix. ECM stiffness induces ROCK activity, which stabilizes SNAIL1 protein indirectly by increasing intracellular tension, integrin clustering and integrin signaling to ERK2 (also known as MAPK1). Increased ERK2 activity leads to nuclear accumulation of SNAIL1, and, thus, avoidance of cytosolic proteasome degradation. SNAIL1 also influences the level and activity of YAP1 in CAFs exposed to a stiff matrix. This work describes a mechanism whereby increased tumor fibrosis can perpetuate activation of CAFs to sustain tumor fibrosis and promote tumor metastasis through regulation of SNAIL1 protein level and activity.

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Section: Hydrogelsmentioning

confidence: 99%

Section: Hydrogelsmentioning

confidence: 99%

Mechanical signals regulate and activate SNAIL1 protein to control the fibrogenic response of cancer-associated fibroblasts

Zhang

Grither

Hove

et al. 2016

Journal of Cell Science

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“…Digital pathology has been successfully applied for objective assessment of overall abundance or activation of various microenvironmental components, including immune cells, 20,23 cancer-associated fibroblasts 24,25 and vessels. [26][27][28] In this section, our primary focus is on methodologies that employ image analysis techniques to assess the spatial context of intra-tumor heterogeneity in three main categories: immune cells, fibroblasts and vessels.…”

Section: Mapping Individual Microenvironmental Componentsmentioning

confidence: 99%

Mapping spatial heterogeneity in the tumor microenvironment: a new era for digital pathology

Heindl

Nawaz

Yuan

2015

Laboratory Investigation

185

148

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The emergent field of digital pathology employing automated image analysis techniques is to revolutionize traditional pathology at the center of clinical diagnostics. Histological images provide important tumor features unavailable in molecular profiling or omics data-the spatial context of tumor and stromal cells at single-cell resolution. Methods to map the spatial and morphological patterns of cancer and normal cells can contribute to a more comprehensive understanding of the highly heterogeneous tumor microenvironment. This review focuses on methods that help expand our knowledge of intra-tumoral spatial heterogeneity of the tumor microenvironment and their potential synergies with molecular profiling technologies.

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“…The cohort and tissue microarray has previously been described in detail (31). Median age at diagnosis was 65 y (range, 34-97 y), and median follow-up time for disease-specific and overall survival was 78 mo.…”

Section: Breast Cancer Patientsmentioning

confidence: 99%

Wnt5a Induces a Tolerogenic Phenotype of Macrophages in Sepsis and Breast Cancer Patients

Bergenfelz

Medrek

Ekström

et al. 2012

The Journal of Immunology

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108

101

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A well-orchestrated inflammatory reaction involves the induction of effector functions and, at a later stage, an active downregulation of this potentially harmful process. In this study we show that under proinflammatory conditions the noncanonical Wnt protein, Wnt5a, induces immunosuppressive macrophages. The suppressive phenotype induced by Wnt5a is associated with induction of IL-10 and inhibition of the classical TLR4-NF-κB signaling. Interestingly, this phenotype closely resembles that observed in reprogrammed monocytes in sepsis patients. The Wnt5a-induced feedback inhibition is active both during in vitro LPS stimulation of macrophages and in patients with sepsis caused by LPS-containing, Gram-negative bacteria. Furthermore, using breast cancer patient tissue microarrays, we find a strong correlation between the expression of Wnt5a in malignant epithelial cells and the frequency of CD163+ anti-inflammatory tumor-associated macrophages. In conclusion, our data point out Wnt5a as a potential target for an efficient therapeutic modality in severe human diseases as diverse as sepsis and malignancy.

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Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice

Cited by 183 publications

References 68 publications

Mechanical signals regulate and activate SNAIL1 protein to control the fibrogenic response of cancer-associated fibroblasts

Mechanical signals regulate and activate SNAIL1 protein to control the fibrogenic response of cancer-associated fibroblasts

Mapping spatial heterogeneity in the tumor microenvironment: a new era for digital pathology

Wnt5a Induces a Tolerogenic Phenotype of Macrophages in Sepsis and Breast Cancer Patients

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