scholarly journals Stiffness increases with myofibroblast content and collagen density in mesenchymal high grade serous ovarian cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Virginie Mieulet ◽  
Camille Garnier ◽  
Yann Kieffer ◽  
Thomas Guilbert ◽  
Fariba Nemati ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Molecular Subtype ◽  
Matrix Remodeling ◽  
High Grade ◽  
Mesenchymal Tumors ◽  
Metabolic Switch ◽  
Desmoplastic Reaction ◽  
Pathway Activation ◽  
Epithelial Compartment ◽  
Tumor Stiffness

AbstractWomen diagnosed with high-grade serous ovarian cancers (HGSOC) are still likely to exhibit a bad prognosis, particularly when suffering from HGSOC of the Mesenchymal molecular subtype (50% cases). These tumors show a desmoplastic reaction with accumulation of extracellular matrix proteins and high content of cancer-associated fibroblasts. Using patient-derived xenograft mouse models of Mesenchymal and Non-Mesenchymal HGSOC, we show here that HGSOC exhibit distinct stiffness depending on their molecular subtype. Indeed, tumor stiffness strongly correlates with tumor growth in Mesenchymal HGSOC, while Non-Mesenchymal tumors remain soft. Moreover, we observe that tumor stiffening is associated with high stromal content, collagen network remodeling, and MAPK/MEK pathway activation. Furthermore, tumor stiffness accompanies a glycolytic metabolic switch in the epithelial compartment, as expected based on Warburg’s effect, but also in stromal cells. This effect is restricted to the central part of stiff Mesenchymal tumors. Indeed, stiff Mesenchymal tumors remain softer at the periphery than at the core, with stromal cells secreting high levels of collagens and showing an OXPHOS metabolism. Thus, our study suggests that tumor stiffness could be at the crossroad of three major processes, i.e. matrix remodeling, MEK activation and stromal metabolic switch that might explain at least in part Mesenchymal HGSOC aggressiveness.

scholarly journals The impact of stroma on the discovery of molecular subtypes and prognostic gene signatures in serous ovarian cancer

2018 ◽  
Author(s):  
Matthew Schwede ◽  
Levi Waldron ◽  
Samuel C. Mok ◽  
Wei Wei ◽  
Azfar Basunia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Stromal Cells ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Gene Signatures ◽  
Prognostic Gene ◽  
Bulk Tissue

AbstractPurposeRecent efforts to improve outcomes for high-grade serous ovarian cancer, a leading cause of cancer death in women, have focused on identifying molecular subtypes and prognostic gene signatures, but existing subtypes have poor cross-study robustness. We tested the contribution of cell admixture in published ovarian cancer molecular subtypes and prognostic gene signatures.Experimental DesignPublic gene expression data, two molecular subtype classifications, and 61 published gene signatures of ovarian cancer were examined. Using microdissected data, we developed gene signatures of ovarian tumor and stroma. Computational simulations of increasing stromal cell proportion were performed by mixing gene expression profiles of paired microdissected ovarian tumor and stroma.ResultsEstablished ovarian cancer molecular subtypes are strongly associated with the cell admixture. Tumors were classified as different molecular subtypes in simulations, when the percentage of stromal cells increased. Stromal gene expression in bulk tumor was weakly prognostic, and in one dataset, increased stroma was associated with anatomic sampling location. Five published prognostic gene signatures were no longer prognostic in a multivariate model that adjusted for stromal content alone.ConclusionsThe discovery that molecular subtypes of high grade serous ovarian cancer is influenced by cell admixture, and stromal cell gene expression is crucial for interpretation and reproduction of ovarian cancer molecular subtypes and gene signatures derived from bulk tissue. Single cell analysis may be required to refine the molecular subtypes of high grade serous ovarian cancer. Because stroma proportion was weakly prognostic, elucidating the role of the tumor microenvironment’s components will be important.Translational relevanceOvarian cancer is a leading cause of cancer death in women in the United States. Although the tumor responds to standard therapy for the majority of patients, it frequently recurs and becomes drug-resistant. Recent efforts have focused on identifying molecular subtypes and prognostic gene signatures of ovarian cancer in order to tailor therapy and improve outcomes. This study demonstrates that molecular subtype identification depends on the ratio of tumor to stroma within the specimen. We show that the specific anatomic location of the biopsy may influence the proportion of stromal involvement and potentially the resulting gene expression pattern. It will be crucial for these factors to be taken into consideration when interpreting and reproducing ovarian cancer molecular subtypes and gene signatures derived using bulk tissue and single cells. Furthermore, it will be important to define the relative proportions of stromal cells and model their prognostic importance in the tumor microenvironment.

scholarly journals The Dynamic Interaction between Extracellular Matrix Remodeling and Breast Tumor Progression

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1046
Author(s):  
Jorge Martinez ◽  
Patricio C. Smith
Keyword(s):  
Extracellular Matrix ◽  
Type I Collagen ◽  
Cell Metabolism ◽  
Breast Tumors ◽  
Extracellular Matrix Remodeling ◽  
Type I ◽  
Matrix Remodeling ◽  
Desmoplastic Reaction ◽  
The Impact

Desmoplastic tumors correspond to a unique tissue structure characterized by the abnormal deposition of extracellular matrix. Breast tumors are a typical example of this type of lesion, a property that allows its palpation and early detection. Fibrillar type I collagen is a major component of tumor desmoplasia and its accumulation is causally linked to tumor cell survival and metastasis. For many years, the desmoplastic phenomenon was considered to be a reaction and response of the host tissue against tumor cells and, accordingly, designated as “desmoplastic reaction”. This notion has been challenged in the last decades when desmoplastic tissue was detected in breast tissue in the absence of tumor. This finding suggests that desmoplasia is a preexisting condition that stimulates the development of a malignant phenotype. With this perspective, in the present review, we analyze the role of extracellular matrix remodeling in the development of the desmoplastic response. Importantly, during the discussion, we also analyze the impact of obesity and cell metabolism as critical drivers of tissue remodeling during the development of desmoplasia. New knowledge derived from the dynamic remodeling of the extracellular matrix may lead to novel targets of interest for early diagnosis or therapy in the context of breast tumors.

scholarly journals Augmentation of Dermal Wound Healing by Adipose Tissue-Derived Stromal Cells (ASC)

2018 ◽  
Vol 5 (4) ◽  
pp. 91 ◽  
Author(s):  
Joris van Dongen ◽  
Martin Harmsen ◽  
Berend van der Lei ◽  
Hieronymus Stevens
Keyword(s):  
Extracellular Matrix ◽  
Wound Healing ◽  
Adipose Tissue ◽  
Stromal Cells ◽  
Randomized Clinical Trials ◽  
Cell Types ◽  
Matrix Remodeling ◽  
Skin Wound Healing ◽  
Dermal Wound Healing ◽  
Dermal Wound

The skin is the largest organ of the human body and is the first line of defense against physical and biological damage. Thus, the skin is equipped to self-repair and regenerates after trauma. Skin regeneration after damage comprises a tightly spatial-temporally regulated process of wound healing that involves virtually all cell types in the skin. Wound healing features five partially overlapping stages: homeostasis, inflammation, proliferation, re-epithelization, and finally resolution or fibrosis. Dysreguled wound healing may resolve in dermal scarring. Adipose tissue is long known for its suppressive influence on dermal scarring. Cultured adipose tissue-derived stromal cells (ASCs) secrete a plethora of regenerative growth factors and immune mediators that influence processes during wound healing e.g., angiogenesis, modulation of inflammation and extracellular matrix remodeling. In clinical practice, ASCs are usually administered as part of fractionated adipose tissue i.e., as part of enzymatically isolated SVF (cellular SVF), mechanically isolated SVF (tissue SVF), or as lipograft. Enzymatic isolation of SVF obtained adipose tissue results in suspension of adipocyte-free cells (cSVF) that lack intact intercellular adhesions or connections to extracellular matrix (ECM). Mechanical isolation of SVF from adipose tissue destructs the parenchyma (adipocytes), which results in a tissue SVF (tSVF) with intact connections between cells, as well as matrix. To date, due to a lack of well-designed prospective randomized clinical trials, neither cSVF, tSVF, whole adipose tissue, or cultured ASCs can be indicated as the preferred preparation procedure prior to therapeutic administration. In this review, we present and discuss current literature regarding the different administration options to apply ASCs (i.e., cultured ASCs, cSVF, tSVF, and lipografting) to augment dermal wound healing, as well as the available indications for clinical efficacy.

scholarly journals Molecular Subtype-Specific Immunocompetent Models of High-Grade Urothelial Carcinoma Reveal Differential Neoantigen Expression and Response to Immunotherapy

2018 ◽  
Vol 78 (14) ◽  
pp. 3954-3968 ◽  
Author(s):  
Ryoichi Saito ◽  
Christof C. Smith ◽  
Takanobu Utsumi ◽  
Lisa M. Bixby ◽  
Jordan Kardos ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Molecular Subtype ◽  
High Grade

scholarly journals Collagen content and extracellular matrix cause cytoskeletal remodelling in pancreatic fibroblasts

2019 ◽  
Vol 16 (154) ◽  
pp. 20190226 ◽  
Author(s):  
Andreas Stylianou ◽  
Vasiliki Gkretsi ◽  
Maria Louca ◽  
Lefteris C. Zacharia ◽  
Triantafyllos Stylianopoulos
Keyword(s):  
Extracellular Matrix ◽  
Stromal Cells ◽  
Smooth Muscle Actin ◽  
Coiled Coil ◽  
Substrate Stiffness ◽  
Tumour Invasion ◽  
Alpha Smooth Muscle Actin ◽  
Desmoplastic Reaction ◽  
Young’S Moduli ◽  
Ecm Proteins

In many solid tumours a desmoplastic reaction takes place, which results in tumour tissue stiffening due to the extensive production of extracellular matrix (ECM) proteins, such as collagen, by stromal cells, mainly fibroblasts (FBs) and cancer-associated fibroblasts (CAFs). In this study, we investigated the effect of collagen stiffness on pancreatic FBs and CAFs, particularly on specific cytoskeleton properties and gene expression involved in tumour invasion. We found that cells become stiffer when they are cultured on stiff substrates and express higher levels of alpha-smooth muscle actin (α-SMA). Also, it was confirmed that on stiff substrates, CAFs are softer than FBs, while on soft substrates they have comparable Young's moduli. Furthermore, the number of spread FBs and CAFs was higher in stiffer substrates, which was also confirmed by Ras-related C3 botulinum toxin substrate 1 ( RAC1 ) mRNA expression, which mediates cell spreading. Although stress fibres in FBs become more oriented on stiff substrates, CAFs have oriented stress fibres regardless of substrate stiffness. Subsequently, we demonstrated that cells' invasion has a differential response to stiffness, which was associated with regulation of Ras homologue family member ( RhoA ) and Rho-associated, coiled-coil containing protein kinase 1 ( ROCK-1 ) mRNA expression. Overall, our results demonstrate that collagen stiffness modulates FBs and CAFs cytoskeleton remodelling and alters their invasion properties.

Identification of prognostic immunophenotypic features in cancer stromal cells of high-grade neuroendocrine carcinomas of the lung

2013 ◽  
Vol 139 (11) ◽  
pp. 1869-1878 ◽  
Author(s):  
Akiko Takahashi ◽  
Genichiro Ishii ◽  
Tomonari Kinoshita ◽  
Tatsuya Yoshida ◽  
Shigeki Umemura ◽  
...  
Keyword(s):  
Stromal Cells ◽  
High Grade ◽  
Neuroendocrine Carcinomas

Hedgehog inhibition impaired platinum response in high-grade serous ovarian cancer harboring high hedgehog ligand expression and mTOR pathway activation.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5583-5583
Author(s):  
Gwo Yaw Ho ◽  
Elizabeth Lieschke ◽  
Elizabeth Kyran ◽  
Kristy Shield-Artin ◽  
Olga Kondrashova ◽  
...  
Keyword(s):  
Cell Line ◽  
Mtor Pathway ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Qrt Pcr ◽  
Gli1 Expression ◽  
Pathway Activation ◽  
In Vivo Treatment

5583 Background: Elevated Glioma-associated Oncogene Homolog-1 (Gli1) protein expression is associated with Hedgehog (Hh) pathway activation in high-grade serous ovarian cancer (HGSOC). Inhibition of Hh signaling in Gli1-overexpressing HGSOC patient-derived xenograft (PDX) inhibited tumour growth, particularly in combination with chemotherapy. Early phase HGSOC clinical trials of vismodegib, a potent Hh inhibitor (SMO inhibitor), were disappointing. We identified a HGSOC PDX harboring both Indian Hh ligand-overexpression and bi-allelic deletion of TSC1, which latter event is reported to derepress the mTOR pathway, driving non-cannonical Gli1 expression. We explored the effect of vismodegib in combination with cisplatin or the mTOR inhibitor, everolimus, in this model. Methods: A cell-line was generated from the well-characterised PDX (identity confirmed by PDX-specific p53 mutation). In vitro response to vismodegib was assessed. qRT-PCR was performed to establish Hh-ligand and Gli1 expression with/without SMO inhibition. A PDX was generated from this cell-line and randomized to in vivo treatment with cisplatin, vismodegib, everolimus or vehicle alone, or vismodegib in combination with cisplatin or everolimus. Results: The HGSOC cell-line was sensitive to vismodegib in vitro (EC50 of 3.5µM) and qRT-PCR analysis revealed down-regulation of Hh-ligand and Gli1 expression following in vitro SMO inhibition, confirming on-target vismodegib activity. In vivo treatment with vismodegib or everolimus alone did not result in reproducible in vivo efficacy. The combination of vismodegib + everolimus caused short-lived responses in 3 of 6 mice. Strikingly, in vivo treatment with vismodegib in combination with cisplatin impaired median survival (19 days) when compared with cisplatin treatment alone (43 days; p = 0.039) due to rapid tumour progression. Conclusions: Combining chemotherapy with Hh inhibition in Hh ligand-overexpressing HGSOC PDX with mTOR pathway activation may be detrimental. These findings highlight the importance of an in-depth understanding of tumour biology in order to effectively combine therapeutic approaches.

Dynamic of molecular subtypes of high‐grade serous ovarian cancer in paired primary and relapsed biopsies.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e17091-e17091
Author(s):  
Elena Ioana Braicu ◽  
Hagen Kulbe ◽  
Felix Dreher ◽  
Eliane T Taube ◽  
Frauke Ringel ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Outcome ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Microarray Gene Expression ◽  
Tissue Samples ◽  
Paired Samples ◽  
Nanostring Technology

e17091 Background: Previously four molecular subtypes of high grade serous ovarian cancer (HGSOC) with distinct biological features and clinical outcome have been described: C1 (mesenchymal), C2 (immunoreactive), C4 (differentiated), and C5 (proliferative). Using Nanostring technique and a minimal signature of 39 classifier genes could reproduce the subtypes identified by microarray gene expression profiling (Leong HS et al. Australian Ovarian Cancer Study. J Pathol. 2015). Methods: We characterized paraffin embedded tissue samples from 279 HGSOC patients for molecular subtypes, utilizing the 39 classifier signature and 9 control genes by Nanostring nCounter Analysis System. From 16 patients paired primary and relapsed samples were available. Only chemonaive primary HGSOC patients were included in the study. FFPEs and clinical data were provided by TOC ( www.toc-network.de ). For each sample, probability scores for the four molecular subtypes (C1, C2, C4, and C5) were calculated. The highest calculated score determined the most likely subtype of the tumor. Results: Of all analyzed primary tumor samples, 88 (31.5%) were classified as C1, 83 (29.8%), 53 (19.0%) and 55 (19.7%) as subtypes C2, C4 and C5, respectively. Our results confirmed data by the AOCS study, which described the distribution of HGSOC with 40.2% (C1), 22.5% (C2), 20.1% (C4) and 17.2% (C5), respectively. Within the paired samples, for 12 of the 16 patients dynamic changes in the molecular subtypes between primary and relapse occurred, while in the remaining 4 patients the phenotype was stable. Conclusions: Molecular subtypes of HGSOC using Nanostring technology with a small panel of classifier genes can be confirmed. Furthermore, the data showed that a change of the established molecular subtype might occur during the evolution of the disease, and therefore translate in a different clinical outcome.

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