bims-ecemfi 2024-03-31 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2024–03–31
28 papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Fibroblast heterogeneity and functions: insights from single-cell sequencing in wound healing, breast cancer, ovarian cancer and melanoma.
Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma or a Metaphor for Heterogeneity: From Single-Cell Analysis to Whole-Body Imaging.
Application of Doxorubicin-loaded PLGA nanoparticles targeting both tumor cells and cancer-associated fibroblasts on 3D human skin equivalents mimicking melanoma and cutaneous squamous cell carcinoma.
Comprehensive single-cell analysis reveals heterogeneity of fibroblast subpopulations in ovarian cancer tissue microenvironment.
Blockage of αvβ3 integrin in 3D culture of triple-negative breast cancer and endothelial cells inhibits migration and discourages endothelial-to-mesenchymal plasticity.
Melanoma-associated fibroblasts in tumor-promotion flammation and antitumor immunity: novel mechanisms and potential immunotherapeutic strategies.
Ezetimibe inhibits the migration and invasion of triple-negative breast cancer cells by targeting TGFβ2 and EMT.
Enhanced epithelial-mesenchymal transition signatures are linked with adverse tumor microenvironment, angiogenesis and worse survival in gastric cancer.
Synthesis and Photopatterning of Synthetic Thiol-Norbornene Hydrogels.
Differential roles of normal and lung cancer-associated fibroblasts in microvascular network formation.
Cancer cell invasion: Caveolae and invadosomes are partners in crime.
Exploring neutrophil functionality in breast cancer progression: A review.
Biophysical interplay between extracellular matrix remodeling and hypoxia signaling in regulating cancer metastasis.
An Overview of Mesenchymal Stem Cell Heterogeneity and Concentration.
Insights into the glioblastoma tumor microenvironment: current and emerging therapeutic approaches.
3D bioprinted tumor model: a prompt and convenient platform for overcoming immunotherapy resistance by recapitulating the tumor microenvironment.
Cellular interactions in tumor microenvironment during breast cancer progression: new frontiers and implications for novel therapeutics.
Anti-IL-8 monoclonal antibodies inhibits the autophagic activity and cancer stem cells maintenance within breast cancer tumor microenvironment.
Characteristics of Cancer Stem Cells and Their Potential Role in Endometrial Cancer.
Editorial: Pulmonary fibrosis and lung carcinogenesis: do myofibroblasts and cancer-associated fibroblasts share a common identity?
The suppression of cell motility through the reduction of FAK activity and expression of cell adhesion proteins by hAMSCs secretome in MDA-MB-231 breast cancer cells.
Development of Anisotropic Electrically Conductive GNP-reinforced PCL-Collagen Scaffold for Enhanced Neurogenic Differentiation under Electrical Stimulation.
Ultra high content analyses of circulating and tumor associated hybrid cells reveal phenotypic heterogeneity.
Chronic hypoxia remodels the tumor microenvironment to support glioma stem cell growth.
Fast-relaxing hydrogels with reversibly tunable mechanics for dynamic cancer cell culture.
Mammary tissue-derived extracellular matrix hydrogels reveal the role of irradiation in driving a pro-tumor and immunosuppressive microenvironment.
Spatially Segregated Macrophage Populations Predict Distinct Outcomes In Colon Cancer.
PANoptosis: bridging apoptosis, pyroptosis, and necroptosis in cancer progression and treatment.

Front Genet. 2024 ;15 1304853

Fibroblast heterogeneity and functions: insights from single-cell sequencing in wound healing, breast cancer, ovarian cancer and melanoma.

Omar Lujano Olazaba, Jeffrey Farrow, Teresa Monkkonen.

  Cancer has been described as the wound that does not heal, in large part due to fibroblast involvement. Activation of cancer-associated fibroblasts (CAFs) contributes to critical features of the tumor microenvironment, including upregulation of key marker proteins, recruitment of immune cells, and deposition of extracellular matrix (ECM)-similar to fibroblast activation in injury-induced wound healing. Prior to the widespread availability of single-cell RNA sequencing (scRNA seq), studies of CAFs or fibroblasts in wound healing largely relied on models guided by individual fibroblast markers, or methods with less resolution to unravel the heterogeneous nature of CAFs and wound healing fibroblasts (especially regarding scarring outcome). Here, insights from the enhanced resolution provided by scRNA sequencing of fibroblasts in normal wound healing, breast cancer, ovarian cancer, and melanoma are discussed. These data have revealed differences in expression of established canonical activation marker genes, epigenetic modifications, fibroblast lineages, new gene and proteins of clinical interest for further experimentation, and novel signaling interactions with other cell types that include spatial information.

Keywords:  breast cancer; cancer associated fibroblast; melanoma; ovarian cancer; single-cell multiomics; wound healing

DOI:  https://doi.org/10.3389/fgene.2024.1304853
Biomedicines. 2024 Mar 06. pii: 591. [Epub ahead of print]12(3):

Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma or a Metaphor for Heterogeneity: From Single-Cell Analysis to Whole-Body Imaging.

Rita Saúde-Conde, Ayça Arçay Öztürk, Kosta Stosic, Oier Azurmendi Senar, Julie Navez, Christelle Bouchart, Tatjana Arsenijevic, Patrick Flamen, Jean-Luc Van Laethem.

  Pancreatic ductal adenocarcinoma (PDAC) represents a formidable challenge due to its aggressive nature and poor prognosis. The tumor microenvironment (TME) in PDAC, characterized by intense stromal desmoplastic reactions and a dominant presence of cancer-associated fibroblasts (CAFs), significantly contributes to therapeutic resistance. However, within the heterogeneous CAF population, fibroblast activation protein (FAP) emerges as a promising target for Gallium-68 FAP inhibitor positron emission tomography (Ga68FAPI-PET) imaging. Notably, 68Ga-FAPI-PET demonstrates promising diagnostic sensitivity and specificity, especially in conjunction with low tracer uptake in non-tumoral tissues. Moreover, it provides valuable insights into tumor-stroma interactions, a critical aspect of PDAC tumorigenesis not adequately visualized through conventional methods. The clinical implications of this innovative imaging modality extend to its potential to reshape treatment strategies by offering a deeper understanding of the dynamic TME. However, while the potential of 68Ga-FAPI-PET is evident, ongoing correlative studies are essential to elucidate the full spectrum of CAF heterogeneity and to validate its impact on PDAC management. This article provides a comprehensive review of CAF heterogeneity in PDAC and explores the potential impact of 68Ga-FAPI-PET on disease management.

Keywords:  Gallium-68 fibroblast activation protein inhibitor positron emission tomography; cancer-associated fibroblast; fibroblast activation protein; heterogeneity; pancreatic cancer

DOI:  https://doi.org/10.3390/biomedicines12030591
Biomater Adv. 2024 Mar 17. pii: S2772-9508(24)00074-8. [Epub ahead of print]160 213831

Application of Doxorubicin-loaded PLGA nanoparticles targeting both tumor cells and cancer-associated fibroblasts on 3D human skin equivalents mimicking melanoma and cutaneous squamous cell carcinoma.

Yuanyuan He, Shidi Wu, Marion Rietveld, Maarten Vermeer, Luis J Cruz, Christina Eich, Abdoelwaheb El Ghalbzouri.

  Nanoparticle (NP) use in cancer therapy is extensively studied in skin cancers. Cancer-associated fibroblasts (CAFs), a major tumor microenvironment (TME) component, promote cancer progression, making dual targeting of cancer cells and CAFs an effective therapy. However, dual NP-based targeting therapy on both tumor cells and CAFs is poorly investigated in skin cancers. Herein, we prepared and characterized doxorubicin-loaded PLGA NPs (DOX@PLGA NPs) and studied their anti-tumor effects on cutaneous melanoma (SKCM)(AN, M14) and cutaneous squamous cell carcinoma (cSCC) (MET1, MET2) cell lines in monolayer, as well as their impact on CAF deactivation. Then, we established 3D full thickness models (FTM) models of SKCM and cSCC using AN or MET2 cells on dermis matrix populated with CAFs respectively, and assessed the NPs' tumor penetration, tumor-killing ability, and CAF phenotype regulation through both topical administration and intradermal injection. The results show that, in monolayer, DOX@PLGA NPs inhibited cancer cell growth and induced apoptosis in a dose- and time-dependent manner, with a weaker effect on CAFs. DOX@PLGA NPs reduced CAF-marker expression and had successful anti-tumor effects in 3D skin cancer FTMs, with decreased tumor-load and invasion. DOX@PLGA NPs also showed great delivery potential in the FTMs and could be used as a platform for future functional study of NPs in skin cancers using human-derived skin equivalents. This study provides promising evidence for the potential of DOX@PLGA NPs in dual targeting therapy for SKCM and cSCC.

Keywords:  Cancer-associated fibroblasts; Doxorubicin; Melanoma; PLGA NPs; Tumor microenvironment; cSCC

DOI:  https://doi.org/10.1016/j.bioadv.2024.213831
Heliyon. 2024 Mar 30. 10(6): e27873

Comprehensive single-cell analysis reveals heterogeneity of fibroblast subpopulations in ovarian cancer tissue microenvironment.

Bo Ding, Zheng Ye, Han Yin, Xin-Yi Hong, Song-Wei Feng, Jing-Yun Xu, Yang Shen.

   Background: Ovarian cancer, as a highly malignant tumor, features the critical involvement of tumor-associated fibroblasts in the ovarian cancer tissue microenvironment. However, due to the apparent heterogeneity within fibroblast subpopulations, the specific functions of these subpopulations in the ovarian cancer tissue microenvironment remain insufficiently elucidated.
Methods: In this study, we integrated single-cell sequencing data from 32 ovarian cancer samples derived from four distinct cohorts and 3226 bulk RNA-seq data from GEO and TCGA-OV cohorts. Utilizing computational frameworks such as Seurat, Monocle 2, Cellchat, and others, we analyzed the characteristics of the ovarian cancer tissue microenvironment, focusing particularly on fibroblast subpopulations and their differentiation trajectories. Employing the CIBERSORTX computational framework, we assessed various cellular components within the ovarian cancer tissue microenvironment and evaluated their associations with ovarian cancer prognosis. Additionally, we conducted Mendelian randomization analysis based on cis-eQTL to investigate causal relationships between gene expression and ovarian cancer.
Results: Through integrative analysis, we identified 13 major cell types present in ovarian cancer tissues, including CD8+ T cells, malignant cells, and fibroblasts. Analysis of the tumor microenvironment (TME) cell proportions revealed a significant increase in the proportion of CD8+ T cells and CD4+ T cells in tumor tissues compared to normal tissues, while fibroblasts predominated in normal tissues. Further subgroup analysis of fibroblasts identified seven subgroups, with the MMP11+Fib subgroup showing the highest activity in the TGFβ signaling pathway. Single-cell analysis suggested that oxidative phosphorylation could be a key pathway driving fibroblast differentiation, and the ATRNL1+KCN + Fib subgroup exhibited chromosomal copy number variations. Prognostic analysis using a large sample size indicated that high infiltration of MMP11+ fibroblasts was associated with poor prognosis in ovarian cancer. SMR analysis identified 132 fibroblast differentiation-related genes, which were linked to pathways such as platinum drug resistance.
Conclusions: In the context of ovarian cancer, fibroblasts expressing MMP11 emerge as the primary drivers of the TGF-beta signaling pathway. Their presence correlates with an increased risk of adverse ovarian prognoses. Additionally, the genetic regulation governing the differentiation of fibroblasts associated with ovarian cancer correlates with the emergence of drug resistance.

Keywords:  Cancer associated fibroblasts; Mendel randomization; Ovarian cancer; Tumor micro-environment; scRNAseq

DOI:  https://doi.org/10.1016/j.heliyon.2024.e27873
Biochem Biophys Rep. 2024 Jul;38 101686

Blockage of αvβ3 integrin in 3D culture of triple-negative breast cancer and endothelial cells inhibits migration and discourages endothelial-to-mesenchymal plasticity.

Bruna Carla Casali, Matheus Pintor Baptista, Bianca Cruz Pachane, Anelise Abreu Cortez, Wanessa Fernanda Altei, Heloísa Sobreiro Selistre-de-Araújo.

  Breast cancer is a relevant cause of mortality in women and its triple-negative subtype (TNBC) is usually associated with poor prognosis. During tumor progression to metastasis, angiogenesis is triggered by the sprouting of endothelial cells from pre-existing vessels by a dynamic chain of events including VE-cadherin downregulation, actin protrusion, and integrin-mediated adhesion, allowing for migration and proliferation. The binding of tumoral and tumor-associated stromal cells with the extracellular matrix through integrins mediates angiogenic processes and certain integrin subtypes, such as the αvβ3 integrin, are upregulated in hypoxic TNBC models. Integrin αvβ3 inhibition by the high-affinity binding disintegrin DisBa-01 was previously demonstrated to induce anti-tumoral and anti-angiogenic responses in traditional 2D cell assays. Here, we investigate the effects of integrin αvβ3 blockage in endothelial and TNBC cells by DisBa-01 in 3D cultures under two oxygen conditions (1% and 20%). 3D cultures created using non-adhesive micromolds with Matrigel were submitted to migration assay in Boyden chambers and fluorescence analysis. DisBa-01 inhibited cell migration in normoxia and hypoxia in both MDA-MB-231 and HUVEC spheroids. Protein levels of integrin αvβ3 were overexpressed in HUVEC spheroids compared to MDA-MB-231 spheroids. In HUVEC 3D cultures, sprouting assays in collagen type I were decreased in normoxia upon DisBa-01 treatment, and VE-cadherin levels were diminished in HUVEC spheroids in hypoxia and upon DisBa-01 treatment. In conclusion, the blockage of integrin αvβ3 by DisBa-01 inhibits cell migration in 3D culture and interferes with tumor-derived responses in different oxygen settings, implicating its crucial role in angiogenesis and tumor progression.

Keywords:  3D culture; Cell migration; Endothelial cell; Triple-negative breast cancer; αvβ3 integrin

DOI:  https://doi.org/10.1016/j.bbrep.2024.101686
Hum Mol Genet. 2024 Mar 27. pii: ddae056. [Epub ahead of print]

Melanoma-associated fibroblasts in tumor-promotion flammation and antitumor immunity: novel mechanisms and potential immunotherapeutic strategies.

Qiujun Zhou, Xiaoliang Jin, Ying Zhao, Yueping Wang, Maocan Tao, Yi Cao, Xiaohu Yin.

  Melanoma, renowned for its aggressive behavior and resistance to conventional treatments, stands as a formidable challenge in the oncology landscape. The dynamic and complex interplay between cancer cells and the tumor microenvironment has gained significant attention, revealing Melanoma-Associated Fibroblasts (MAFs) as central players in disease progression. The heterogeneity of MAFs endows them with a dual role in melanoma. This exhaustive review seeks to not only shed light on the multifaceted roles of MAFs in orchestrating tumor-promoting inflammation but also to explore their involvement in antitumor immunity. By unraveling novel mechanisms underlying MAF functions, this review aims to provide a comprehensive understanding of their impact on melanoma development. Additionally, it delves into the potential of leveraging MAFs for innovative immunotherapeutic strategies, offering new avenues for enhancing treatment outcomes in the challenging realm of melanoma therapeutics.

Keywords:  CAF; antitumor immunity; immunotherapy; melanoma-associated fibroblasts; tumor-promotion flammation

DOI:  https://doi.org/10.1093/hmg/ddae056
FEBS Open Bio. 2024 Mar 26.

Ezetimibe inhibits the migration and invasion of triple-negative breast cancer cells by targeting TGFβ2 and EMT.

Lingkai Kong, Qinyu He, Ding Ma, Weiwei Shi, Qilei Xin, Chunping Jiang, Junhua Wu.

  The important role of cholesterol in tumor metastasis has been widely studied in recent years. Ezetimibe is currently the only selective cholesterol uptake inhibitor on the market. Here, we explored the effect of ezetimibe on breast cancer metastasis by studying its impact on breast cancer cell migration, invasion, and epithelial-mesenchymal transition (EMT). Differential gene expression analysis and validation were also carried out to compare ezetimibe-treated and untreated breast cancer cells. Finally, breast cancer cells overexpressing TGFβ2 were constructed, and the effect of TGFβ2 on the migration and invasion of ezetimibe-treated breast cancer cells was examined. Our results show that ezetimibe treatment of breast cancer cells inhibited cell migration, invasion, and EMT, and it significantly suppressed the expression of TGFβ2. Overexpression of TGFβ2 reversed the inhibitory effect of ezetimibe on the migration and invasion of breast cancer cells. Taken together, our results suggest that ezetimibe might be a potential candidate for the treatment of breast cancer metastasis.

Keywords:  TGFβ2; breast cancer; cholesterol; ezetimibe; metastasis

DOI:  https://doi.org/10.1002/2211-5463.13797
Cancer Gene Ther. 2024 Mar 26.

Enhanced epithelial-mesenchymal transition signatures are linked with adverse tumor microenvironment, angiogenesis and worse survival in gastric cancer.

Masanori Oshi, Arya Mariam Roy, Li Yan, Sachika Kinoshita, Yuko Tamura, Takashi Kosaka, Hirotoshi Akiyama, Chikara Kunisaki, Kazuaki Takabe, Itaru Endo.

Epithelial-mesenchymal transition (EMT) is a crucial mechanism that facilitates cancer cell metastasis. Despite its importance, the clinical significance of EMT in gastric cancer (GC) patients has yet to be clearly demonstrated. For gauging the extent of EMT in GC, we employed gene set variation analysis to score 807 patient samples from two large cohorts: TCGA and GSE84437. In both cohorts, EMT high GC showed a significant association with worse overall survival (hazard ratio (HR) = 1.74, p = 0.011 and HR = 2.01, p < 0.001, respectively). This association was stronger when considering the EMT signature score compared to the individual expressions of EMT-related genes (CDH1, CDH2, VIM, and FN1). While the EMT signature level did not differ among various cancers, high EMT signature specifically correlated with survival in GC alone. Mucinous and diffuse histological types exhibited higher EMT levels compared to others (p < 0.001), and the EMT signature level was correlated with tumor depth and AJCC stage (all p < 0.001). Interestingly, the EMT score was an independent factor for overall and disease-specific survival (multivariate; p = 0.006 and 0.032, respectively). EMT high GC displayed a lower fraction of Th1 cells and a higher fraction of dendritic cells, M1 macrophages and several stromal cells. EMT high GC exhibited an inverse correlation with cell proliferation-related gene sets. While they significantly enriched multiple pro-cancerous gene sets, such as TGF-β signaling, hypoxia, and angiogenesis. The presence of EMT signature in a bulk tumor was linked to TGF-β signaling, hypoxia, and angiogenesis, and was also associated with poorer survival outcomes in GC patients.

DOI: https://doi.org/10.1038/s41417-024-00756-w
Gels. 2024 Feb 23. pii: 164. [Epub ahead of print]10(3):

Synthesis and Photopatterning of Synthetic Thiol-Norbornene Hydrogels.

Umu S Jalloh, Arielle Gsell, Kirstene A Gultian, James MacAulay, Abigail Madden, Jillian Smith, Luke Siri, Sebastián L Vega.

  Hydrogels are a class of soft biomaterials and the material of choice for a myriad of biomedical applications due to their biocompatibility and highly tunable mechanical and biochemical properties. Specifically, light-mediated thiol-norbornene click reactions between norbornene-modified macromers and di-thiolated crosslinkers can be used to form base hydrogels amenable to spatial biochemical modifications via subsequent light reactions between pendant norbornenes in the hydrogel network and thiolated peptides. Macromers derived from natural sources (e.g., hyaluronic acid, gelatin, alginate) can cause off-target cell signaling, and this has motivated the use of synthetic macromers such as poly(ethylene glycol) (PEG). In this study, commercially available 8-arm norbornene-modified PEG (PEG-Nor) macromers were reacted with di-thiolated crosslinkers (dithiothreitol, DTT) to form synthetic hydrogels. By varying the PEG-Nor weight percent or DTT concentration, hydrogels with a stiffness range of 3.3 kPa-31.3 kPa were formed. Pendant norbornene groups in these hydrogels were used for secondary reactions to either increase hydrogel stiffness (by reacting with DTT) or to tether mono-thiolated peptides to the hydrogel network. Peptide functionalization has no effect on bulk hydrogel mechanics, and this confirms that mechanical and biochemical signals can be independently controlled. Using photomasks, thiolated peptides can also be photopatterned onto base hydrogels, and mesenchymal stem cells (MSCs) attach and spread on RGD-functionalized PEG-Nor hydrogels. MSCs encapsulated in PEG-Nor hydrogels are also highly viable, demonstrating the ability of this platform to form biocompatible hydrogels for 2D and 3D cell culture with user-defined mechanical and biochemical properties.

Keywords:  8-arm PEG; photopatterning; synthetic hydrogels; thiol-norbornene

DOI:  https://doi.org/10.3390/gels10030164
APL Bioeng. 2024 Mar;8(1): 016120

Differential roles of normal and lung cancer-associated fibroblasts in microvascular network formation.

Naveen R Natesh, Pankaj Mogha, Alan Chen, Scott J Antonia, Shyni Varghese.

Perfusable microvascular networks offer promising three-dimensional in vitro models to study normal and compromised vascular tissues as well as phenomena such as cancer cell metastasis. Engineering of these microvascular networks generally involves the use of endothelial cells stabilized by fibroblasts to generate robust and stable vasculature. However, fibroblasts are highly heterogenous and may contribute variably to the microvascular structure. Here, we study the effect of normal and cancer-associated lung fibroblasts on the formation and function of perfusable microvascular networks. We examine the influence of cancer-associated fibroblasts on microvascular networks when cultured in direct (juxtacrine) and indirect (paracrine) contacts with endothelial cells, discovering a generative inhibition of microvasculature in juxtacrine co-cultures and a functional inhibition in paracrine co-cultures. Furthermore, we probed the secreted factors differential between cancer-associated fibroblasts and normal human lung fibroblasts, identifying several cytokines putatively influencing the resulting microvasculature morphology and functionality. These findings suggest the potential contribution of cancer-associated fibroblasts in aberrant microvasculature associated with tumors and the plausible application of such in vitro platforms in identifying new therapeutic targets and/or agents that can prevent formation of aberrant vascular structures.

DOI: https://doi.org/10.1063/5.0188238
Curr Biol. 2024 Mar 25. pii: S0960-9822(24)00148-9. [Epub ahead of print]34(6): R244-R246

Cancer cell invasion: Caveolae and invadosomes are partners in crime.

Laura Sotodosos-Alonso, Miguel A Del Pozo.

During cancer progression, tumor cells need to disseminate by remodeling the extracellular tumor matrix. A recent study sheds light on the intricate cooperation between caveolae and invadosomes that facilitates the spread of cancer cells.

DOI: https://doi.org/10.1016/j.cub.2024.02.006
Medicine (Baltimore). 2024 Mar 29. 103(13): e37654

Exploring neutrophil functionality in breast cancer progression: A review.

Emmanuel Ifeanyi Obeagu, Getrude Uzoma Obeagu.

Breast cancer remains a pressing global health concern, with a myriad of intricate factors contributing to its development, progression, and heterogeneity. Among these multifaceted elements, the role of immune cells within the tumor microenvironment is gaining increasing attention. In this context, neutrophils, traditionally regarded as the first responders to infections, are emerging as noteworthy participants in the complex landscape of breast cancer. This paper seeks to unravel the intricate and multifaceted role of neutrophils in breast cancer. Neutrophils, classically known for their phagocytic and pro-inflammatory functions, are now recognized for their involvement in promoting or restraining tumor growth. While their presence within the tumor microenvironment may exert antitumor effects through immune surveillance and cytotoxic activities, these innate immune cells can also facilitate tumor progression by fostering an immunosuppressive milieu, promoting angiogenesis, and aiding metastatic dissemination. The intricacies of neutrophil-tumor cell interactions, signaling pathways, and mechanisms governing their recruitment to the tumor site are explored in detail. Challenges and gaps in current knowledge are acknowledged, and future directions for research are outlined. This review underscores the dynamic and context-dependent role of neutrophils in breast cancer and emphasizes the significance of unraveling their multifaceted contributions. As we delve into the complexities of the immune landscape in breast cancer, a deeper understanding of the warriors within, the neutrophils, presents exciting prospects for the development of novel therapeutic strategies and a more comprehensive approach to breast cancer management.

DOI: https://doi.org/10.1097/MD.0000000000037654
Front Cell Dev Biol. 2024 ;12 1335636

Biophysical interplay between extracellular matrix remodeling and hypoxia signaling in regulating cancer metastasis.

Sun-Ah Lee, Gi-Ju Cho, Doyoung Kim, Dong-Hwee Kim.

  Mechanical properties of the tumor microenvironment play a critical role in cancer progression by activation of cancer mechano-responses. The biophysical interactions between cancer cells and their dynamic microenvironment are attributed to force-dependent alterations in molecular pathways that trigger the structural reorganization of intracellular organelles and their associated genetic modifications. Recent studies underscore the role of oxygen concentration in cancer metastasis. Suppressed oxygen levels promote the development of invasive phenotypes and aggressive proliferation of cancer cells, accompanied by remodeling of tumor microenvironment encompassing the modulation of physical settings of extracellular matrix. This review summarizes the role of biophysical interactions between cancer cells and their surroundings in determining cancer progression. Biophysical interpretation of the tumor microenvironment and cancer progression could provide further insights into the development of novel biomedical technologies for therapeutic cancer treatment.

Keywords:  ECM remodeling; cancer biophysics; cancer metastasis; hypoxia; mechano-regulation; mechano-signaling; tumor-microenvironment

DOI:  https://doi.org/10.3389/fcell.2024.1335636
Pharmaceuticals (Basel). 2024 Mar 07. pii: 350. [Epub ahead of print]17(3):

An Overview of Mesenchymal Stem Cell Heterogeneity and Concentration.

Elvira Maličev, Katerina Jazbec.

  Mesenchymal stem cells (MSCs) are of great interest in cell therapies due to the immunomodulatory and other effects they have after autologous or allogeneic transplantation. In most clinical applications, a high number of MSCs is required; therefore, the isolated MSC population must be expanded in the cell culture until the desired number is reached. Analysing freshly isolated MSCs is challenging due to their rareness and heterogeneity, which is noticeable among donors, tissues, and cell subpopulations. Although the phenotype of MSCs in tissue can differ from those of cultured cells, phenotyping and counting are usually performed only after MSC proliferation. As MSC applicability is a developing and growing field, there is a need to implement phenotyping and counting methods for freshly isolated MSCs, especially in new one-step procedures where isolated cells are implanted immediately without cell culturing. Only by analysing harvested cells can we correctly evaluate such studies. This review describes multilevel heterogeneity and concentrations of MSCs and different strategies for phenotype determination and enumeration of freshly isolated MSCs.

Keywords:  concentration; heterogeneity; mesenchymal stem cells; phenotype; tissue source

DOI:  https://doi.org/10.3390/ph17030350
Front Pharmacol. 2024 ;15 1355242

Insights into the glioblastoma tumor microenvironment: current and emerging therapeutic approaches.

Dev Kumar Tripathy, Lakshmi Priya Panda, Suryanarayan Biswal, Kalpana Barhwal.

  Glioblastoma (GB) is an intrusive and recurrent primary brain tumor with low survivability. The heterogeneity of the tumor microenvironment plays a crucial role in the stemness and proliferation of GB. The tumor microenvironment induces tumor heterogeneity of cancer cells by facilitating clonal evolution and promoting multidrug resistance, leading to cancer cell progression and metastasis. It also plays an important role in angiogenesis to nourish the hypoxic tumor environment. There is a strong interaction of neoplastic cells with their surrounding microenvironment that comprise several immune and non-immune cellular components. The tumor microenvironment is a complex network of immune components like microglia, macrophages, T cells, B cells, natural killer (NK) cells, dendritic cells and myeloid-derived suppressor cells, and non-immune components such as extracellular matrix, endothelial cells, astrocytes and neurons. The prognosis of GB is thus challenging, making it a difficult target for therapeutic interventions. The current therapeutic approaches target these regulators of tumor micro-environment through both generalized and personalized approaches. The review provides a summary of important milestones in GB research, factors regulating tumor microenvironment and promoting angiogenesis and potential therapeutic agents widely used for the treatment of GB patients.

Keywords:  angiogenesis; blood-brain barrier; glioblastoma; immunotherapy; therapeutic approaches; tumor microenvironment

DOI:  https://doi.org/10.3389/fphar.2024.1355242
Cell Oncol (Dordr). 2024 Mar 23.

3D bioprinted tumor model: a prompt and convenient platform for overcoming immunotherapy resistance by recapitulating the tumor microenvironment.

Zhangyi Zhang, Xuebo Chen, Sujie Gao, Xuedong Fang, Shengnan Ren.

   BACKGROUND: Cancer immunotherapy is receiving worldwide attention for its induction of an anti-tumor response. However, it has had limited efficacy in some patients who acquired resistance. The dynamic and sophisticated complexity of the tumor microenvironment (TME) is the leading contributor to this clinical dilemma. Through recapitulating the physiological features of the TME, 3D bioprinting is a promising research tool for cancer immunotherapy, which preserves in vivo malignant aggressiveness, heterogeneity, and the cell-cell/matrix interactions. It has been reported that application of 3D bioprinting holds potential to address the challenges of immunotherapy resistance and facilitate personalized medication.
CONCLUSIONS AND PERSPECTIVES: In this review, we briefly summarize the contributions of cellular and noncellular components of the TME in the development of immunotherapy resistance, and introduce recent advances in 3D bioprinted tumor models that served as platforms to study the interactions between tumor cells and the TME. By constructing multicellular 3D bioprinted tumor models, cellular and noncellular crosstalk is reproduced between tumor cells, immune cells, fibroblasts, adipocytes, and the extracellular matrix (ECM) within the TME. In the future, by quickly preparing 3D bioprinted tumor models with patient-derived components, information on tumor immunotherapy resistance can be obtained timely for clinical reference. The combined application with tumoroid or other 3D culture technologies will also help to better simulate the complexity and dynamics of tumor microenvironment in vitro. We aim to provide new perspectives for overcoming cancer immunotherapy resistance and inspire multidisciplinary research to improve the clinical application of 3D bioprinting technology.

Keywords:  Acquired resistance; Bioprinting; Cancer immunotherapy; In vitro tumor model; Personalized medication

DOI:  https://doi.org/10.1007/s13402-024-00935-9
Front Immunol. 2024 ;15 1302587

Cellular interactions in tumor microenvironment during breast cancer progression: new frontiers and implications for novel therapeutics.

Tosin Akinsipe, Rania Mohamedelhassan, Ayuba Akinpelu, Satyanarayana R Pondugula, Panagiotis Mistriotis, L Adriana Avila, Amol Suryawanshi.

  The breast cancer tumor microenvironment (TME) is dynamic, with various immune and non-immune cells interacting to regulate tumor progression and anti-tumor immunity. It is now evident that the cells within the TME significantly contribute to breast cancer progression and resistance to various conventional and newly developed anti-tumor therapies. Both immune and non-immune cells in the TME play critical roles in tumor onset, uncontrolled proliferation, metastasis, immune evasion, and resistance to anti-tumor therapies. Consequently, molecular and cellular components of breast TME have emerged as promising therapeutic targets for developing novel treatments. The breast TME primarily comprises cancer cells, stromal cells, vasculature, and infiltrating immune cells. Currently, numerous clinical trials targeting specific TME components of breast cancer are underway. However, the complexity of the TME and its impact on the evasion of anti-tumor immunity necessitate further research to develop novel and improved breast cancer therapies. The multifaceted nature of breast TME cells arises from their phenotypic and functional plasticity, which endows them with both pro and anti-tumor roles during tumor progression. In this review, we discuss current understanding and recent advances in the pro and anti-tumoral functions of TME cells and their implications for developing safe and effective therapies to control breast cancer progress.

Keywords:  breast cancer; immune cells; metastasis; stroma; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1302587
Breast Dis. 2024 ;43(1): 37-49

Anti-IL-8 monoclonal antibodies inhibits the autophagic activity and cancer stem cells maintenance within breast cancer tumor microenvironment.

Seham Abou Shousha, Eman Medhat, Suzan Baheeg, Yasmine Shahine.

   BACKGROUND: Breast cancer tumor microenvironment (TME) is a promising target for immunotherapy. Autophagy, and cancer stem cells (CSCs) maintenance are essential processes involved in tumorigenesis, tumor survival, invasion, and treatment resistance. Overexpression of angiogenic chemokine interleukin-8 (IL-8) in breast cancer TME is associated with oncogenic signaling pathways, increased tumor growth, metastasis, and poor prognosis.
OBJECTIVE: Thus, we aimed to investigate the possible anti-tumor effect of neutralizing antibodies against IL-8 by evaluating its efficacy on autophagic activity and breast CSC maintenance.
METHODS: IL-8 monoclonal antibody supplemented tumor tissue culture systems from 15 females undergoing mastectomy were used to evaluate the expression of LC3B as a specific biomarker of autophagy and CD44, CD24 as cell surface markers of breast CSCs using immunofluorescence technique.
RESULTS: Our results revealed that anti-IL-8 mAb significantly decreased the level of LC3B in the cultured tumor tissues compared to its non-significant decrease in the normal breast tissues.Anti-IL-8 mAb also significantly decreased the CD44 expression in either breast tumors or normal cultured tissues. While it caused a non-significant decrease in CD24 expression in cultured breast tumor tissue and a significant decrease in its expression in the corresponding normal ones.
CONCLUSIONS: Anti-IL-8 monoclonal antibody exhibits promising immunotherapeutic properties through targeting both autophagy and CSCs maintenance within breast cancer TME.

Keywords:  Breast cancer; anti-IL-8 mab; autophagy; cancer stem cells; tumor microenvironment

DOI:  https://doi.org/10.3233/BD-230052
Cancers (Basel). 2024 Mar 07. pii: 1083. [Epub ahead of print]16(6):

Characteristics of Cancer Stem Cells and Their Potential Role in Endometrial Cancer.

Karolina Frąszczak, Bartłomiej Barczyński.

  Endometrial cancer is one of most common types of gynaecological tumours in developing countries. It has been suggested that cancer stem cells play an important role in the development of endometrial cancer. These are a subset of highly tumorigenic cells with similar features to normal stem cells (unlimited proliferation, multi-potential differentiation, self-renewal, aggressiveness, invasion, recurrence, and chemo- and endocrine therapy resistance). Wnt/β-catenin, Hedghog, and Notch1 are the most frequently activated pathways in endometrial cancer stem cells. The presence of cancer stem cells is associated with the resistance to chemotherapy caused by different mechanisms. Various markers, including CD24, CD40, CD44, CD9, CD133, and CD 166, have been identified on the surface of these cells. A higher expression of such markers translates into enhanced tumorigenicity. However, there is no strong evidence showing that any of these identified markers can be used as the universal marker for endometrial cancer stem cells. Growing data from genomic and proteomic profiling shed some light on the understanding of the molecular basis of cancers in humans and the role of cancer stem cells. However, there is much left to discover. Therefore, more studies are needed to fully uncover their functional mechanisms in order to prevent the development and recurrence of cancer, as well as to enhance treatment effectiveness.

Keywords:  CD117; CD133; CD44; cancer stem cells; endometrial cancer

DOI:  https://doi.org/10.3390/cancers16061083
Front Oncol. 2024 ;14 1389532

Editorial: Pulmonary fibrosis and lung carcinogenesis: do myofibroblasts and cancer-associated fibroblasts share a common identity?

Daniela de Totero, Emanuela Barisione, Enrico Clini.



Keywords:  cancer-associated fibroblasts; extracellular matrix; lung cancer; myofibroblasts; pulmonary fibrosis

DOI:  https://doi.org/10.3389/fonc.2024.1389532
Invest New Drugs. 2024 Mar 27.

The suppression of cell motility through the reduction of FAK activity and expression of cell adhesion proteins by hAMSCs secretome in MDA-MB-231 breast cancer cells.

Fatemeh Safari, Setareh Bararpour, Fatemeh Omidi Chomachaei.

  Breast cancer is a leading cause of death in women worldwide. Cancer therapy based on stem cells is considered as a novel and promising platform. In the present study, we explore the therapeutic effects of human amniotic mesenchymal stromal cells (hAMSCs) through the reduction of focal adhesion kinase (FAK) activity, SHP-2, and cell adhesion proteins such as Paxillin, Vinculin, Fibronectin, Talin, and integrin αvβ3 expression in MDA-MB-231 breast cancer cells. For this purpose, we employed a co-culture system using 6-well plate transwell. After 72 h, hAMSCs-treated MDA-MB-231 breast cancer cells, the activity of focal adhesion kinase (FAK) and the expression of SHP-2 and cell adhesion proteins such as Paxillin, Vinculin, Fibronectin, Talin, and integrin αvβ3 expression were analyzed using western blot. The shape and migration of cells were also analyzed. Based on our results, a significant reduction in tumor cell motility through downregulation of the tyrosine phosphorylation level of FAK (at Y397 and Y576/577 sites) and cell adhesion expression in MDA-MB-231 breast cancer cells was demonstrated. Our findings indicate that hAMSCS secretome has therapeutic effects on cancer cell migration through downregulation of FAK activity and expression of cell adhesion proteins.

Keywords:  Breast cancer cells; Cell adhesion proteins; FAK activity; HAMSCs

DOI:  https://doi.org/10.1007/s10637-024-01434-2
Chem Asian J. 2024 Mar 28. e202400061

Development of Anisotropic Electrically Conductive GNP-reinforced PCL-Collagen Scaffold for Enhanced Neurogenic Differentiation under Electrical Stimulation.

Souvik Ghosh, Partha Roy, Debrupa Lahiri.

  The internal electric field of the human body plays a crucial role in regulating various biological processes, such as, cellular interactions, embryonic development and the healing process. Electrical stimulation (ES) modulates cytoskeleton and calcium ion activities to restore nervous system functioning. When exposed to electrical fields, stem cells respond similarly to neurons, muscle cells, blood vessel linings, and connective tissue (fibroblasts), depending on their environment. This study develops cost-effective electroconductive scaffolds for regenerative medicine. This was achieved by incorporating carboxy functionalized graphene nanoplatelets (GNPs) into a Polycaprolactone (PCL)-collagen matrix. ES was used to assess the scaffolds' propensity to boost neuronal differentiation from MSCs. This study reported that aligned GNP-reinforced PCL-Collagen scaffolds demonstrate substantial MSC differentiation with ES. This work effectively develops scaffolds using a simple, cost-effective synthesis approach. The direct coupling approach generated a homogeneous electric field to stimulate cells cultivated on GNP-reinforced scaffolds. The scaffolds exhibited improved mechanical and electrical characteristics, as a result of the reinforcement with carbon nanofillers. In vitro results suggest that electrical stimulation helps differentiation of mesenchymal stem-like cells (MSC-like) towards neuronal. This finding holds great potential for the development of effective treatments for tissue injuries related to the nervous system.

Keywords:  Graphene nanoplatelets; cellular differentiation; electrical stimulation; neuron-like cells; scaffold

DOI:  https://doi.org/10.1002/asia.202400061
Sci Rep. 2024 03 28. 14(1): 7350

Ultra high content analyses of circulating and tumor associated hybrid cells reveal phenotypic heterogeneity.

Riley M Whalen, Ashley N Anderson, Jocelyn A Jones, Zachary Sims, Young Hwan Chang, Michel A Nederlof, Melissa H Wong, Summer L Gibbs.

  Persistently high, worldwide mortality from cancer highlights the unresolved challenges of disease surveillance and detection that impact survival. Development of a non-invasive, blood-based biomarker would transform survival from cancer. We demonstrate the functionality of ultra-high content analyses of a newly identified population of tumor cells that are hybrids between neoplastic and immune cells in patient matched tumor and peripheral blood specimens. Using oligonucleotide conjugated antibodies (Ab-oligo) permitting cyclic immunofluorescence (cyCIF), we present analyses of phenotypes among tumor and peripheral blood hybrid cells. Interestingly, the majority of circulating hybrid cell (CHC) subpopulations were not identified in tumor-associated hybrids. These results highlight the efficacy of ultra-high content phenotypic analyses using Ab-oligo based cyCIF applied to both tumor and peripheral blood specimens. The combination of a multiplex phenotypic profiling platform that is gentle enough to analyze blood to detect and evaluate disseminated tumor cells represents a novel approach to exploring novel tumor biology and potential utility for developing the population as a blood-based biomarker in cancer.

Keywords:  Cancer biomarker; Cancer progression; Circulating hybrid cell; Colorectal cancer; Cyclic immunofluorescence; Oligonucleotide-conjugated antibody; Pancreatic cancer

DOI:  https://doi.org/10.1038/s41598-024-57381-8
Acta Neuropathol Commun. 2024 Mar 25. 12(1): 46

Chronic hypoxia remodels the tumor microenvironment to support glioma stem cell growth.

J G Nicholson, S Cirigliano, R Singhania, C Haywood, M Shahidi Dadras, M Yoshimura, D Vanderbilt, B Liechty, H A Fine.

Cerebral organoids co-cultured with patient derived glioma stem cells (GLICOs) are an experimentally tractable research tool useful for investigating the role of the human brain tumor microenvironment in glioblastoma. Here we describe long-term GLICOs, a novel model in which COs are grown from embryonic stem cell cultures containing low levels of GSCs and tumor development is monitored over extended durations (ltGLICOs). Single-cell profiling of ltGLICOs revealed an unexpectedly long latency period prior to GSC expansion, and that normal organoid development was unimpaired by the presence of low numbers of GSCs. However, as organoids age they experience chronic hypoxia and oxidative stress which remodels the tumor microenvironment to promote GSC expansion. Receptor-ligand modelling identified astrocytes, which secreted various pro-tumorigenic ligands including FGF1, as the primary cell type for GSC crosstalk and single-cell multi-omic analysis revealed these astrocytes were under the control of ischemic regulatory networks. Functional validation confirmed hypoxia as a driver of pro-tumorigenic astrocytic ligand secretion and that GSC expansion was accelerated by pharmacological induction of oxidative stress. When controlled for genotype, the close association between glioma aggressiveness and patient age has very few proposed biological explanations. Our findings indicate that age-associated increases in cerebral vascular insufficiency and associated regional chronic cerebral hypoxia may contribute to this phenomenon.

DOI: https://doi.org/10.1186/s40478-024-01755-6
Biomater Adv. 2024 Mar 15. pii: S2772-9508(24)00072-4. [Epub ahead of print]159 213829

Fast-relaxing hydrogels with reversibly tunable mechanics for dynamic cancer cell culture.

Yee Yee Khine, Han Nguyen, Favour Afolabi, Chien-Chi Lin.

The mechanics of the tumor microenvironment (TME) significantly impact disease progression and the efficacy of anti-cancer therapeutics. While it is recognized that advanced in vitro cancer models will benefit cancer research, none of the current engineered extracellular matrices (ECM) adequately recapitulate the highly dynamic TME. Through integrating reversible boronate-ester bonding and dithiolane ring-opening polymerization, we fabricated synthetic polymer hydrogels with tumor-mimetic fast relaxation and reversibly tunable elastic moduli. Importantly, the crosslinking and dynamic stiffening of matrix mechanics were achieved in the absence of a photoinitiator, often the source of cytotoxicity. Central to this strategy was Poly(PEGA-co-LAA-co-AAPBA) (PELA), a highly defined polymer synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. PELA contains dithiolane for initiator-free gel crosslinking, stiffening, and softening, as well as boronic acid for complexation with diol-containing polymers to give rise to tunable viscoelasticity. PELA hydrogels were highly cytocompatible for dynamic culture of patient-derived pancreatic cancer cells. It was found that the fast-relaxing matrix induced mesenchymal phenotype of cancer cells, and dynamic matrix stiffening restricted tumor spheroid growth. Moreover, this new dynamic viscoelastic hydrogel system permitted sequential stiffening and softening to mimic the physical changes of TME.

DOI: https://doi.org/10.1016/j.bioadv.2024.213829
Biomaterials. 2024 Mar 21. pii: S0142-9612(24)00065-6. [Epub ahead of print]308 122531

Mammary tissue-derived extracellular matrix hydrogels reveal the role of irradiation in driving a pro-tumor and immunosuppressive microenvironment.

Tian Zhu, Steven M Alves, Arianna Adamo, Xiaona Wen, Kevin C Corn, Anastasia Shostak, Shereena Johnson, Nicholas D Shaub, Shannon E Martello, Benjamin C Hacker, Antonio D'Amore, Rizia Bardhan, Marjan Rafat.

  Radiation therapy (RT) is essential for triple negative breast cancer (TNBC) treatment. However, patients with TNBC continue to experience recurrence after RT. The role of the extracellular matrix (ECM) of irradiated breast tissue in tumor recurrence is still unknown. In this study, we evaluated the structure, molecular composition, and mechanical properties of irradiated murine mammary fat pads (MFPs) and developed ECM hydrogels from decellularized tissues (dECM) to assess the effects of RT-induced ECM changes on breast cancer cell behavior. Irradiated MFPs were characterized by increased ECM deposition and fiber density compared to unirradiated controls, which may provide a platform for cell invasion and proliferation. ECM component changes in collagens I, IV, and VI, and fibronectin were observed following irradiation in both MFPs and dECM hydrogels. Encapsulated TNBC cell proliferation and invasive capacity was enhanced in irradiated dECM hydrogels. In addition, TNBC cells co-cultured with macrophages in irradiated dECM hydrogels induced M2 macrophage polarization and exhibited further increases in proliferation. Our study establishes that the ECM in radiation-damaged sites promotes TNBC invasion and proliferation as well as an immunosuppressive microenvironment. This work represents an important step toward elucidating how changes in the ECM after RT contribute to breast cancer recurrence.

Keywords:  Breast cancer; Invasion; M2 macrophages; Proliferation; Radiation therapy; dECM hydrogels

DOI:  https://doi.org/10.1016/j.biomaterials.2024.122531
Cancer Discov. 2024 Mar 28.

Spatially Segregated Macrophage Populations Predict Distinct Outcomes In Colon Cancer.

Magdalena Matusiak, John W Hickey, David G P van IJzendoorn, Guolan Lu, Lukasz Kidzinski, Shirley Zhu, Deana R C Colburg, Bogdan Luca, Darci J Phillips, Sky W Brubaker, Gregory W Charville, Jeanne Shen, Kyle M Loh, Derick K Okwan-Duodu, Garry P Nolan, Aaron M Newman, Robert B West, Matt van de Rijn.

Tumor-associated macrophages are transcriptionally heterogeneous, but the spatial distribution and cell interactions that shape macrophage tissue roles remain poorly characterized. Here, we spatially resolve five distinct human macrophage populations in normal and malignant human breast and colon tissue and reveal their cellular associations. This spatial map reveals that distinct macrophage populations reside in spatially segregated micro-environmental niches with conserved cellular compositions that are repeated across healthy and diseased tissue. We show that IL4I1+ macrophages phagocytose dying cells in areas with high cell turnover and predict good outcome in colon cancer. In contrast, SPP1+ macrophages are enriched in hypoxic and necrotic tumor regions and portend worse outcome in colon cancer. A subset of FOLR2+ macrophages is embedded in plasma cell niches. NLRP3+ macrophages co-localize with neutrophils and activate an inflammasome in tumors. Our findings indicate that a limited number of unique human macrophage niches function as fundamental building blocks in tissue.

DOI: https://doi.org/10.1158/2159-8290.CD-23-1300
Cancer Gene Ther. 2024 Mar 29.

PANoptosis: bridging apoptosis, pyroptosis, and necroptosis in cancer progression and treatment.

Jie Gao, Anying Xiong, Jiliu Liu, Xiaolan Li, Junyi Wang, Lei Zhang, Yao Liu, Ying Xiong, Guoping Li, Xiang He.

This comprehensive review explores the intricate mechanisms of PANoptosis and its implications in cancer. PANoptosis, a convergence of apoptosis, pyroptosis, and necroptosis, plays a crucial role in cell death and immune response regulation. The study delves into the molecular pathways of each cell death mechanism and their crosstalk within PANoptosis, emphasizing the shared components like caspases and the PANoptosome complex. It highlights the significant role of PANoptosis in various cancers, including respiratory, digestive, genitourinary, gliomas, and breast cancers, showing its impact on tumorigenesis and patient survival rates. We further discuss the interwoven relationship between PANoptosis and the tumor microenvironment (TME), illustrating how PANoptosis influences immune cell behavior and tumor progression. It underscores the dynamic interplay between tumors and their microenvironments, focusing on the roles of different immune cells and their interactions with cancer cells. Moreover, the review presents new breakthroughs in cancer therapy, emphasizing the potential of targeting PANoptosis to enhance anti-tumor immunity. It outlines various strategies to manipulate PANoptosis pathways for therapeutic purposes, such as targeting key signaling molecules like caspases, NLRP3, RIPK1, and RIPK3. The potential of novel treatments like immunogenic PANoptosis-initiated therapies and nanoparticle-based strategies is also explored.

DOI: https://doi.org/10.1038/s41417-024-00765-9