Cell-extracellular Matrix Interactions Research Articles

Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood-brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood-brain barrier disruption.

Talin variant P229S compromises integrin activation and associates with multifaceted clinical symptoms.

Adhesion of cells to the extracellular matrix (ECM) must be exquisitely coordinated to enable development and tissue homeostasis. Cell-ECM interactions are regulated by multiple signalling pathways that coordinate the activation state of the integrin family of ECM receptors. The protein talin is pivotal in this process, and talin's simultaneous interactions with the cytoplasmic tails of the integrins and the plasma membrane are essential to enable robust, dynamic control of integrin activation and cell-ECM adhesion. Here, we report the identification of a de novo heterozygous c.685C>T (p.Pro229Ser) variant in the TLN1 gene from a patient with a complex phenotype. The mutation is located in the talin head region at the interface between the F2 and F3 domains. The characterization of this novel p.P229S talin variant reveals the disruption of adhesion dynamics that result from disturbance of the F2-F3 domain interface in the talin head. Using biophysical, computational and cell biological techniques, we find that the variant perturbs the synergy between the integrin-binding F3 and the membrane-binding F2 domains, compromising integrin activation, adhesion and cell migration. Whilst this remains a variant of uncertain significance, it is probable that the dysregulation of adhesion dynamics we observe in cells contributes to the multifaceted clinical symptoms of the patient and may provide insight into the multitude of cellular processes dependent on talin-mediated adhesion dynamics.

Dense discrete phase model for tumor cell growth analysis in fluid environments

Cell-cell and cell-extracellular matrix interactions play a major role in tumor growth, which involves complex molecular intercommunications. We have developed a single-cell computational model in which fluid dynamics and cell-cell interaction are coupled to evaluate the growth of cancer cells in fluidic environments. The results demonstrate that, once the cell concentration increases, the cell-cell interaction increases, decreasing cell maturation time and increasing tumor growth rate.

Polymeric nanoparticles surface-complexed with boric acid actively target solid tumors overexpressing sialic acid

Sialic acid is a fundamental component of the tumor microenvironment, modulates cell–cell and cell-extracellular matrix interactions and is associated with bad prognosis and clinical outcomes in different cancers. Capitalizing on the ability of boric acid to form cyclic esters with diols, in this work, we design self-assembled multi-micellar colloidal systems of an amphiphilic poly(vinyl alcohol)-g-poly(methyl methacrylate) copolymer surface-modified with boric acid for the active targeting of solid tumors that overexpress sialic acid. Nanoparticles display sizes in the 100–200 nm range and a spherical morphology, as determined by dynamic light scattering and high resolution-scanning electron microscopy, respectively. The uptake and anti-proliferative activity are assessed in 2D and 3D models of rhabdomyosarcoma in vitro. Surface boration increases the nanoparticle permeability and uptake, especially in rhabdomyosarcoma spheroids that overexpress sialic acid to a greater extent than 2D cultures. The biodistribution of non-borated and borated nanoparticles upon intravenous injection to a subcutaneous rhabdomyosarcoma murine xenograft model confirm a statistically significant increase in the intertumoral accumulation of the modified nanocarriers with respect to the unmodified counterparts and a sharp decrease in major clearance organs such as the liver. Overall, our results highlight the promise of these borated nanomaterials to actively target hypersialylated solid tumors.

New Perspectives on the Role of Integrin-Linked Kinase (ILK) Signaling in Cancer Metastasis.

Simple SummaryToday, the vast majority of deaths from cancer are due to cancer metastasis. Metastasis requires that cancer cells escape from the initial tumor, travel through blood vessels, and form new tumors in distant host tissues. Integrin-linked kinase (ILK) is overexpressed by many types of cancer cells and provides both structural and signaling functions that are important for successful metastasis. Here, we discuss recent findings that show how ILK is involved in promoting physical changes important for cell motility and invasion, and how ILK relays signals to other machinery components during metastasis, including interactions with components of the immune system and communication between cancer cells and normal cells, to affect the process of metastasis. We also discuss the contribution of ILK to therapeutic resistance and examine efforts to target ILK for the treatment of metastatic disease.Cancer metastasis is a major barrier to the long-term survival of cancer patients. In cancer cells, integrin engagement downstream of cell-extracellular matrix (ECM) interactions results in the recruitment of cytoskeletal and signaling molecules to form multi-protein complexes to promote processes critical for metastasis. One of the major functional components of these complexes is Integrin Linked Kinase (ILK). Here, we discuss recent advances in our understanding of the importance of ILK as a signaling effector in processes linked to tumor progression and metastasis. New mechanistic insights as to the role of ILK in cellular plasticity, epithelial mesenchymal transition (EMT), migration, and invasion, including the impact of ILK on the formation of invadopodia, filopodia-like protrusions (FLPs), and Neutrophil Extracellular Trap (NET)-induced motility are highlighted. Recent findings detailing the contribution of ILK to therapeutic resistance and the importance of ILK as a potentially therapeutically tractable vulnerability in both solid tumors and hematologic malignancies are discussed. Indeed, pharmacologic inhibition of ILK activity using specific small molecule inhibitors is effective in curtailing the contribution of ILK to these processes, potentially offering a novel therapeutic avenue for inhibiting critical steps in the metastatic cascade leading to reduced drug resistance and increased therapeutic efficacy.

In Vitro Models of Blood and Lymphatic Vessels-Connecting Tissues and Immunity.

Blood and lymphatic vessels are regulators of physiological processes, including oxygenation and fluid transport. Both vessels are ubiquitous throughout the body and are critical for sustaining tissue homeostasis. The complexity of each vessel's processes has limited the understanding of exactly how the vessels maintain their functions. Both vessels have been shown to be involved in the pathogenesis of many diseases, including cancer metastasis, and it is crucial to probe further specific mechanisms involved. In vitro models are developed to better understand blood and lymphatic physiological functions and their mechanisms. In this review, blood and lymphatic in vitro model systems, including 2D and 3D designs made using Transwells, microfluidic devices, organoid cultures, and various other methods, are described. Models studying endothelial cell-extracellular matrix interactions, endothelial barrier properties, transendothelial transport and cell migration, lymph/angiogenesis, vascular inflammation, and endothelial-cancer cell interactions are particularly focused. While the field has made significant progress in modeling and understanding lymphatic and blood vasculature, more models that include coculture of multiple cell types, complex extracellular matrix, and 3D morphologies, particularly for models mimicking disease states, will help further the understanding of the role of blood and lymphatic vasculature in health and disease.

Stem Cell Based Approaches to Modulate the Matrix Milieu in Vascular Disorders.

The extracellular matrix (ECM) represents a complex and dynamic framework for cells, characterized by tissue-specific biophysical, mechanical, and biochemical properties. ECM components in vascular tissues provide structural support to vascular cells and modulate their function through interaction with specific cell-surface receptors. ECM–cell interactions, together with neurotransmitters, cytokines, hormones and mechanical forces imposed by blood flow, modulate the structural organization of the vascular wall. Changes in the ECM microenvironment, as in post-injury degradation or remodeling, lead to both altered tissue function and exacerbation of vascular pathologies. Regeneration and repair of the ECM are thus critical toward reinstating vascular homeostasis. The self-renewal and transdifferentiating potential of stem cells (SCs) into other cell lineages represents a potentially useful approach in regenerative medicine, and SC-based approaches hold great promise in the development of novel therapeutics toward ECM repair. Certain adult SCs, including mesenchymal stem cells (MSCs), possess a broader plasticity and differentiation potential, and thus represent a viable option for SC-based therapeutics. However, there are significant challenges to SC therapies including, but not limited to cell processing and scaleup, quality control, phenotypic integrity in a disease milieu in vivo, and inefficient delivery to the site of tissue injury. SC-derived or -inspired strategies as a putative surrogate for conventional cell therapy are thus gaining momentum. In this article, we review current knowledge on the patho-mechanistic roles of ECM components in common vascular disorders and the prospects of developing adult SC based/inspired therapies to modulate the vascular tissue environment and reinstate vessel homeostasis in these disorders.

Abstract 176: Development of PDX-derived spheroids using LifeGel, an innovative 3D cell culture technology

Abstract One of the biggest challenges in preclinical oncology is the lack of models faithfully recapitulating the physiological and pathophysiological features of the native tumor. PDXs (Patient-Derived Xenografts), developed in immune-compromised mice, have proven their relevance in the study of aberrations leading to the development and progression of cancer, to the mechanisms linked to tumor resistance and to the identification of novel therapies. Despite being a fundamental step to generate new knowledge on cancer, the use of PDXs shows some technical disadvantages such as long engraftment time and/or low growth rate, thus raising economic and ethical concerns. Huge efforts are being done to develop cell-based alternatives systems reproducing the tumor complexity combined with suitable methods. To this aim, we have developed 50+ PDX-derived cell lines (PDXDCs) from our proprietary 200+ PDX collection. These lines are currently used as two-dimensional (2D) cultures to perform drug screening in an affordable, timewise, and cost-effective way. While well designed, drug-tailored 2D screenings can predict drug behavior in vivo, they present limitations as they are unable to reproduce cell-cell and cell-extracellular matrix interactions, two important parameters that contribute to the regulation of drug accessibility and oxygen diffusion in vivo. To encompass those limitations and give access to a wider range of experimental methods we have generated three-dimensional (3D) cell culture models by taking advantage of LifeGel technology, consisting of protein-based hydrogels that modulate matrix density and stiffness to mimic the organ of origin-specific extracellular environment. Thanks to its versatility we successfully developed spheroid cultures from PDXDCs from various indications, including breast cancer cells from different histological subtypes. Tumor cells plated on LifeGel adopted 3D spheroid-like structures in a few days. These structures showed heterogeneous morphology and size depending on the tumor type and the hydrogel composition. As spheroids can be passaged in vitro by digestion, we could easily expand them and perform drug screening that will be presented and compared to 2D and in vivo results. The aim of this project is to develop a collection of PDX-derived spheroids recapitulating PDXs characteristics. This collection will give the opportunity to perform high-content drugs screening to select the best candidate drugs to be retained for further preclinical in vivo studies. Citation Format: Agnieszka Pietrzyk, Emilie Indersie, Olivier Deas, Jean-Gabriel Judde, Marcin Krzykawski, Stefano Cairo. Development of PDX-derived spheroids using LifeGel, an innovative 3D cell culture technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 176.

NELL1 Regulates the Matrisome to Promote Osteosarcoma Progression.

NELL1 modulates the sarcoma matrisome to promote tumor growth, invasion, and metastasis, identifying the matrix-associated protein as an orchestrator of cell-ECM interactions in sarcomagenesis and disease progression.

Collagen gel contraction assays: From modelling wound healing to quantifying cellular interactions with three-dimensional extracellular matrices

Cells respond to and actively remodel the extracellular matrix (ECM). The dynamic and bidirectional interaction between cells and ECM, especially their mechanical interactions, has been found to play an essential role in triggering a series of complex biochemical and biomechanical signal pathways and in regulating cellular functions and behaviours. The collagen gel contraction assay (CGCA) is a widely used method to investigate cell–ECM interactions in 3D environments and provides a mechanically associated readout reflecting 3D cellular contractility. In this review, we summarize various versions of CGCA, with an emphasis on recent high-throughput and low-consumption CGCA techniques. More importantly, we focus on the technique of force monitoring during the contraction of collagen gel, which provides a quantitative characterization of the overall forces generated by all the resident cells in the collagen hydrogel. Accordingly, we present recent biological applications of the CGCA, which have expanded from the initial wound healing model to other studies concerning cell–ECM interactions, including fibrosis, cancer, tissue repair and the preparation of biomimetic microtissues.

Three-Dimensional 3D Culture Models in Gynecological and Breast Cancer Research.

Traditional two-dimensional (2D) monolayer cell cultures have long been the gold standard for cancer biology research. However, their ability to accurately reflect the molecular mechanisms of tumors occurring in vivo is limited. Recent development of three-dimensional (3D) cell culture models facilitate the possibility to better recapitulate several of the biological and molecular characteristics of tumors in vivo, such as cancer cells heterogeneity, cell-extracellular matrix interactions, development of a hypoxic microenvironment, signaling pathway activities depending on contacts with extracellular matrix, differential growth kinetics, more accurate drugs response, and specific gene expression and epigenetic patterns. In this review, we discuss the utilization of different types of 3D culture models including spheroids, organotypic models and patient-derived organoids in gynecologic cancers research, as well as its potential applications in oncological research mainly for screening drugs with major physiological and clinical relevance. Moreover, microRNAs regulation of cancer hallmarks in 3D cell cultures from different types of cancers is discussed.

Three-Dimensional Organotypic Cultures Reshape the microRNAs Transcriptional Program in Breast Cancer Cells.

Simple SummaryThree-dimensional (3D) cell cultures have several advantages over conventional monolayer two-dimensional (2D) cultures as they can better mimic tumor biology. This study delineates the changes in microRNAs (miRNAs) expression patterns of breast cancer cells cultured in 3D and 2D conditions. 3D organotypic cultures showed morphological changes such as cell–cell and cell–extracellular matrix interactions associated with a loss of polarity and reorganization on bulk structures in both basal Hs578T and luminal T47D breast cancer cells. Data indicate that downregulated miRNAs in Hs578T 3D cultures, relative to the 2D condition, contribute to a positive regulation of biological processes such as response to hypoxia and focal adhesion, whereas overexpressed miRNAs were related to negative regulation of the cell cycle. Remarkably, the reprogramming of miRNAs transcriptional profile was accompanied by changes in the expression of key miRNA/mRNA coregulation networks, such as miR-935/HIF-1A, which correlated with the expression found in clinical breast tumors and predicted poor patient outcomes. These data have implications in our understanding of cancer biology and impact the miRNA/mRNA regulatory axes of cells grown in 3D cultures. Our data represent a guide for novel miRNAs candidates for functional analysis, including the response to therapy and biomarkers discovery in breast cancer.The 3D organotypic cultures, which depend on the growth of cells over the extracellular matrix (ECM) used as a scaffold, can better mimic several characteristics of solid cancers that influence tumor biology and the response to drug therapies. Most of our current knowledge on cancer is derived from studies in 2D cultures, which lack the ECM-mediated microenvironment. Moreover, the role of miRNAs that is critical for fine-tuning of gene expression is poorly understood in 3D cultures. The aim of this study was to compare the miRNA expression profiles of breast cancer cells grown in 2D and 3D conditions. On an on-top 3D cell culture model using a basement membrane matrix enriched with laminin, collagen IV, entactin, and heparin-sulfate proteoglycans, the basal B (Hs578T) and luminal (T47D) breast cancer cells formed 3D spheroid-like stellate and rounded mass structures, respectively. Morphological changes in 3D cultures were observed as cell stretching, cell–cell, and cell–ECM interactions associated with a loss of polarity and reorganization on bulk structures. Interestingly, we found prolongations of the cytoplasmic membrane of Hs578T cells similar to tunneled nanotubes contacting between neighboring cells, suggesting the existence of cellular intercommunication processes and the possibility of fusion between spheroids. Expression profiling data revealed that 354 miRNAs were differentially expressed in 3D relative to 2D cultures in Hs578T cells. Downregulated miRNAs may contribute to a positive regulation of genes involved in hypoxia, catabolic processes, and focal adhesion, whereas overexpressed miRNAs modulate genes involved in negative regulation of the cell cycle. Target genes of the top ten modulated miRNAs were selected to construct miRNA/mRNA coregulation networks. Around 502 interactions were identified for downregulated miRNAs, including miR-935/HIF1A and miR-5189-3p/AKT that could contribute to cell migration and the response to hypoxia. Furthermore, the expression levels of miR-935 and its target HIF1A correlated with the expression found in clinical tumors and predicted poor outcomes. On the other hand, 416 interactions were identified for overexpressed miRNAs, including miR-6780b-5p/ANKRD45 and miR-7641/CDK4 that may result in cell proliferation inhibition and cell cycle arrest in quiescent layers of 3D cultures. In conclusion, 3D cultures could represent a suitable model that better resembles the miRNA transcriptional programs operating in tumors, with implications not only in the understanding of basic cancer biology in 3D microenvironments, but also in the identification of novel biomarkers of disease and potential targets for personalized therapies in cancer.

Focal adhesion-mediated cell anchoring and migration: from in vitro to in vivo.

Cell-extracellular matrix interactions have been studied extensively using cells cultured in vitro. These studies indicate that focal adhesion (FA)-based cell-extracellular matrix interactions are essential for cell anchoring and cell migration. Whether FAs play a similarly important role in vivo is less clear. Here, we summarize the formation and function of FAs in cultured cells and review how FAs transmit and sense force in vitro. Using examples from animal studies, we also describe the role of FAs in cell anchoring during morphogenetic movements and cell migration in vivo. Finally, we conclude by discussing similarities and differences in how FAs function in vitro and in vivo.

Pathobiology of Airway Remodeling in Asthma: The Emerging Role of Integrins.

Airway remodeling is a complex clinical feature of asthma that involves long-term disruption and modification of airway architecture, which contributes significantly to airway hyperresponsiveness (AHR) and lung function decline. It is characterized by thickening of the airway smooth muscle layer, deposition of a matrix below the airway epithelium, resulting in subepithelial fibrosis, changes within the airway epithelium, leading to disruption of the barrier, and excessive mucous production and angiogenesis within the airway wall. Airway remodeling contributes to stiffer and less compliant airways in asthma and leads to persistent, irreversible airflow obstruction. Current asthma treatments aim to reduce airway inflammation and exacerbations but none are targeted towards airway remodeling. Inhibiting the development of airway remodeling or reversing established remodeling has the potential to dramatically improve symptoms and disease burden in asthmatic patients. Integrins are a family of transmembrane heterodimeric proteins that serve as the primary receptors for extracellular matrix (ECM) components, mediating cell–cell and cell–ECM interactions to initiate intracellular signaling cascades. Cells present within the lungs, including structural and inflammatory cells, express a wide and varying range of integrin heterodimer combinations and permutations. Integrins are emerging as an important regulator of inflammation, repair, remodeling, and fibrosis in the lung, particularly in chronic lung diseases such as asthma. Here, we provide a comprehensive summary of the current state of knowledge on integrins in the asthmatic airway and how these integrins promote the remodeling process, and emphasize their potential involvement in airway disease.

Comparative evaluation and Immunohistochemical expression of Syndecan-1 in Ameloblastoma and Dentigerous cyst.

Background: Syndecans are type-1 heparan sulphate proteoglycans which play significant role in cell-cell and cell-extracellular matrix interaction. Syndecans are involved in tooth development and differentiation of mesenchymal cells. Amongst odontogenic lesions, ameloblastomas and dentigerous cysts are routinely encountered lesions with difference in treatment modality based on its aggressiveness. The objective of the present research was to study and compare immunohistochemical expression of syndecan-1 in ameloblastoma and dentigerous cyst. Method: 40 retrospectively diagnosed cases of ameloblastomas and dentigerous cysts were immunohistochemically stained against syndecan-1. The intensity of immunostaining and percentage of positive cells was assessed by three independent blind observers. Weighted kappa test was used to find out inter-observer reliability. Comparative evaluation of syndecan-1 expression between the two lesions was done using student t-test.
 Results: There was statistically significant difference between the mean of score for intensity, mean of score for percentage of positive cells and total mean score of syndecan-1 between ameloblastoma and dentigerous cyst. Conclusion: Syndecan-1 may be involved in aetiopathogenesis of odontogenic lesions like ameloblastoma and dentigerous cyst. Also, weak expression in ameloblastoma indicates that tumor invasion and aggressiveness is related to cell adhesion molecule like syndecan-1.

Intrinsic Differences in Spatiotemporal Organization and Stromal Cell Interactions Between Isogenic Lung Cancer Cells of Epithelial and Mesenchymal Phenotypes Revealed by High-Dimensional Single-Cell Analysis of Heterotypic 3D Spheroid Models.

The lack of inadequate preclinical models remains a limitation for cancer drug development and is a primary contributor to anti-cancer drug failures in clinical trials. Heterotypic multicellular spheroids are three-dimensional (3D) spherical structures generated by self-assembly from aggregates of two or more cell types. Compared to traditional monolayer cell culture models, the organization of cells into a 3D tissue-like structure favors relevant physiological conditions with chemical and physical gradients as well as cell-cell and cell-extracellular matrix (ECM) interactions that recapitulate many of the hallmarks of cancer in situ. Epidermal growth factor receptor (EGFR) mutations are prevalent in non-small cell lung cancer (NSCLC), yet various mechanisms of acquired resistance, including epithelial-to-mesenchymal transition (EMT), limit the clinical benefit of EGFR tyrosine kinase inhibitors (EGFRi). Improved preclinical models that incorporate the complexity induced by epithelial-to-mesenchymal plasticity (EMP) are urgently needed to advance new therapeutics for clinical NSCLC management. This study was designed to provide a thorough characterization of multicellular spheroids of isogenic cancer cells of various phenotypes and demonstrate proof-of-principle for the applicability of the presented spheroid model to evaluate the impact of cancer cell phenotype in drug screening experiments through high-dimensional and spatially resolved imaging mass cytometry (IMC) analyses. First, we developed and characterized 3D homotypic and heterotypic spheroid models comprising EGFRi-sensitive or EGFRi-resistant NSCLC cells. We observed that the degree of EMT correlated with the spheroid generation efficiency in monocultures. In-depth characterization of the multicellular heterotypic spheroids using immunohistochemistry and high-dimensional single-cell analyses by IMC revealed intrinsic differences between epithelial and mesenchymal-like cancer cells with respect to self-sorting, spatiotemporal organization, and stromal cell interactions when co-cultured with fibroblasts. While the carcinoma cells harboring an epithelial phenotype self-organized into a barrier sheet surrounding the fibroblasts, mesenchymal-like carcinoma cells localized to the central hypoxic and collagen-rich areas of the compact heterotypic spheroids. Further, deep-learning-based single-cell segmentation of IMC images and application of dimensionality reduction algorithms allowed a detailed visualization and multiparametric analysis of marker expression across the different cell subsets. We observed a high level of heterogeneity in the expression of EMT markers in both the carcinoma cell populations and the fibroblasts. Our study supports further application of these models in pre-clinical drug testing combined with complementary high-dimensional single-cell analyses, which in turn can advance our understanding of the impact of cancer-stroma interactions and epithelial phenotypic plasticity on innate and acquired therapy resistance in NSCLC.

The Interplay between Cell-Extracellular Matrix Interaction and Mitochondria Dynamics in Cancer.

Simple SummaryMitochondria are essential cellular organelles, involved in controlling energy production, cell metabolism, cell growth, and cell death. Since cellular functions are de-regulated in cancer, it is not surprising that mitochondria dysfunctions have been observed in this disease. One key aspect in controlling tumor formation and progression is the interaction between the cancer cells and their surrounding environment, known as the tumor microenvironment. The extracellular matrix is an abundant component of the tumor microenvironment and it has been shown to affect tumor initiation and progression. Here, we will explore how the interaction between cancer cells and the extracellular matrix impinges on mitochondria function during cancer progression.The tumor microenvironment, in particular the extracellular matrix (ECM), plays a pivotal role in controlling tumor initiation and progression. In particular, the interaction between cancer cells and the ECM promotes cancer cell growth and invasion, leading to the formation of distant metastasis. Alterations in cancer cell metabolism is a key hallmark of cancer, which is often associated with alterations in mitochondrial dynamics. Recent research highlighted that, changes in mitochondrial dynamics are associated with cancer migration and metastasis—these has been extensively reviewed elsewhere. However, less is known about the interplay between the extracellular matrix and mitochondria functions. In this review, we will highlight how ECM remodeling associated with tumorigenesis contribute to the regulation of mitochondrial function, ultimately promoting cancer cell metabolic plasticity, able to fuel cancer invasion and metastasis.

In Situ Super-Resolution Imaging of Organoids and Extracellular Matrix Interactions via Phototransfer by Allyl Sulfide Exchange-Expansion Microscopy (PhASE-ExM).

3D organoid models have recently seen a boom in popularity, as they can better recapitulate the complexity of multicellular organs compared to other in vitro culture systems. However, organoids are difficult to image because of the limited penetration depth of high-resolution microscopes and depth-dependent light attenuation, which can limit the understanding of signal transduction pathways and characterization of intimate cell-extracellular matrix (ECM) interactions. To overcome these challenges, phototransfer by allyl sulfide exchange-expansion microscopy (PhASE-ExM) is developed, enabling optical clearance and super-resolution imaging of organoids and their ECM in 3D. PhASE-ExM uses hydrogels prepared via photoinitiated polymerization, which is advantageous as it decouples monomer diffusion into thick organoid cultures from the hydrogel fabrication. Apart from compatibility with organoids cultured in Matrigel, PhASE-ExM enables 3.25× expansion and super-resolution imaging of organoids cultured in synthetic poly(ethylene glycol) (PEG) hydrogels crosslinked via allyl-sulfide groups (PEG-AlS) through simultaneous photopolymerization and radical-mediated chain-transfer reactions that complete in <70 s. Further, PEG-AlS hydrogels can be in situ softened to promote organoid crypt formation, providing a super-resolution imaging platform both for pre- and post-differentiated organoids. Overall, PhASE-ExM is a useful tool to decipher organoid behavior by enabling sub-micrometer scale, 3D visualization of proteins and signal transduction pathways.

Molecular Mechanisms of Tumor Immunomodulation in the Microenvironment of Colorectal Cancer.

Colorectal cancer remains one of the most important health challenges in our society. The development of cancer immunotherapies has fostered the need to better understand the anti-tumor immune mechanisms at play in the tumor microenvironment and the strategies by which the tumor escapes them. In this review, we provide an overview of the molecular interactions that regulate tumor inflammation. We particularly discuss immunomodulatory cell-cell interactions, cell-soluble factor interactions, cell-extracellular matrix interactions and cell-microbiome interactions. While doing so, we highlight relevant examples of tumor immunomodulation in colorectal cancer.

21P Transcriptomic mapping of integrins and immune activation in high-grade serous ovarian cancer

Integrins, transmembrane receptors that mediade cell-extracellular matrix and cell-cell interaction, have been linked to cancer features. A less explores function of integrins in cancer is their role in leukocyte homing and activation. Understanding their role and relationship with immune infiltrates and immune checkpoints is an area of interest in cancer research.