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Nature Communications Dec 2020Immunosuppressive tumor microenvironment (TME) and ascites-derived spheroids in ovarian cancer (OC) facilitate tumor growth and progression, and also pose major...
Immunosuppressive tumor microenvironment (TME) and ascites-derived spheroids in ovarian cancer (OC) facilitate tumor growth and progression, and also pose major obstacles for cancer therapy. The molecular pathways involved in the OC-TME interactions, how the crosstalk impinges on OC aggression and chemoresistance are not well-characterized. Here, we demonstrate that tumor-derived UBR5, an E3 ligase overexpressed in human OC associated with poor prognosis, is essential for OC progression principally by promoting tumor-associated macrophage recruitment and activation via key chemokines and cytokines. UBR5 is also required to sustain cell-intrinsic β-catenin-mediated signaling to promote cellular adhesion/colonization and organoid formation by controlling the p53 protein level. OC-specific targeting of UBR5 strongly augments the survival benefit of conventional chemotherapy and immunotherapies. This work provides mechanistic insights into the novel oncogene-like functions of UBR5 in regulating the OC-TME crosstalk and suggests that UBR5 is a potential therapeutic target in OC treatment for modulating the TME and cancer stemness.
Topics: Adult; Aged; Animals; Ascites; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Disease Models, Animal; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Humans; Immune Checkpoint Inhibitors; Immunotherapy, Adoptive; Macrophages, Peritoneal; Mice; Mice, Knockout; Middle Aged; Ovarian Neoplasms; Paracrine Communication; Peritoneal Neoplasms; Primary Cell Culture; Prognosis; Receptors, Chimeric Antigen; Spheroids, Cellular; Tumor Escape; Tumor Microenvironment; Ubiquitin-Protein Ligases
PubMed: 33293516
DOI: 10.1038/s41467-020-20140-0 -
The Journal of Clinical Investigation Aug 2021Ovarian cancer is the leading cause of gynecological malignancy-related deaths, due to its widespread intraperitoneal metastases and acquired chemoresistance....
Ovarian cancer is the leading cause of gynecological malignancy-related deaths, due to its widespread intraperitoneal metastases and acquired chemoresistance. Mesothelial cells are an important cellular component of the ovarian cancer microenvironment that promote metastasis. However, their role in chemoresistance is unclear. Here, we investigated whether cancer-associated mesothelial cells promote ovarian cancer chemoresistance and stemness in vitro and in vivo. We found that osteopontin is a key secreted factor that drives mesothelial-mediated ovarian cancer chemoresistance and stemness. Osteopontin is a secreted glycoprotein that is clinically associated with poor prognosis and chemoresistance in ovarian cancer. Mechanistically, ovarian cancer cells induced osteopontin expression and secretion by mesothelial cells through TGF-β signaling. Osteopontin facilitated ovarian cancer cell chemoresistance via the activation of the CD44 receptor, PI3K/AKT signaling, and ABC drug efflux transporter activity. Importantly, therapeutic inhibition of osteopontin markedly improved the efficacy of cisplatin in both human and mouse ovarian tumor xenografts. Collectively, our results highlight mesothelial cells as a key driver of ovarian cancer chemoresistance and suggest that therapeutic targeting of osteopontin may be an effective strategy for enhancing platinum sensitivity in ovarian cancer.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Epithelium; Female; Humans; Mice; Neoplastic Stem Cells; Organoids; Osteopontin; Ovarian Neoplasms; Paracrine Communication; Signal Transduction; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 34396988
DOI: 10.1172/JCI146186 -
Nature Apr 2020The initiation of an intestinal tumour is a probabilistic process that depends on the competition between mutant and normal epithelial stem cells in crypts. Intestinal...
The initiation of an intestinal tumour is a probabilistic process that depends on the competition between mutant and normal epithelial stem cells in crypts. Intestinal stem cells are closely associated with a diverse but poorly characterized network of mesenchymal cell types. However, whether the physiological mesenchymal microenvironment of mutant stem cells affects tumour initiation remains unknown. Here we provide in vivo evidence that the mesenchymal niche controls tumour initiation in trans. By characterizing the heterogeneity of the intestinal mesenchyme using single-cell RNA-sequencing analysis, we identified a population of rare pericryptal Ptgs2-expressing fibroblasts that constitutively process arachidonic acid into highly labile prostaglandin E (PGE). Specific ablation of Ptgs2 in fibroblasts was sufficient to prevent tumour initiation in two different models of sporadic, autochthonous tumorigenesis. Mechanistically, single-cell RNA-sequencing analyses of a mesenchymal niche model showed that fibroblast-derived PGE drives the expansion οf a population of Sca-1 reserve-like stem cells. These express a strong regenerative/tumorigenic program, driven by the Hippo pathway effector Yap. In vivo, Yap is indispensable for Sca-1 cell expansion and early tumour initiation and displays a nuclear localization in both mouse and human adenomas. Using organoid experiments, we identified a molecular mechanism whereby PGE promotes Yap dephosphorylation, nuclear translocation and transcriptional activity by signalling through the receptor Ptger4. Epithelial-specific ablation of Ptger4 misdirected the regenerative reprogramming of stem cells and prevented Sca-1 cell expansion and sporadic tumour initiation in mutant mice, thereby demonstrating the robust paracrine control of tumour-initiating stem cells by PGE-Ptger4. Analyses of patient-derived organoids established that PGE-PTGER4 also regulates stem-cell function in humans. Our study demonstrates that initiation of colorectal cancer is orchestrated by the mesenchymal niche and reveals a mechanism by which rare pericryptal Ptgs2-expressing fibroblasts exert paracrine control over tumour-initiating stem cells via the druggable PGE-Ptger4-Yap signalling axis.
Topics: Adaptor Proteins, Signal Transducing; Animals; Antigens, Ly; Arachidonic Acid; Carcinogenesis; Cell Cycle Proteins; Cell Proliferation; Colorectal Neoplasms; Cyclooxygenase 2; Dinoprostone; Female; Fibroblasts; Humans; Intestinal Mucosa; Intestines; Male; Membrane Proteins; Mesoderm; Mice; Neoplastic Stem Cells; Organoids; Paracrine Communication; Receptors, Prostaglandin E, EP4 Subtype; Single-Cell Analysis; Stem Cell Niche; YAP-Signaling Proteins
PubMed: 32322056
DOI: 10.1038/s41586-020-2166-3 -
Current Osteoporosis Reports Aug 2020The purpose of this review is to describe the current state of our thinking regarding bone-muscle interactions beyond the mechanical perspective. (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to describe the current state of our thinking regarding bone-muscle interactions beyond the mechanical perspective.
RECENT FINDINGS
Recent and prior evidence has begun to dissect many of the molecular mechanisms that bone and muscle use to communicate with each other and to modify each other's function. Several signaling factors produced by muscle and bone have emerged as potential mediators of these biochemical/molecular interactions. These include muscle factors such as myostatin, Irisin, BAIBA, IL-6, and the IGF family and the bone factors FGF-23, Wnt1 and Wnt3a, PGE2, FGF9, RANKL, osteocalcin, and sclerostin. The identification of these signaling molecules and their underlying mechanisms offers the very real and exciting possibility that new pharmaceutical approaches can be developed that will permit the simultaneous treatments of diseases that often occur in combination, such as osteoporosis and sarcopenia.
Topics: Adaptor Proteins, Signal Transducing; Aminoisobutyric Acids; Bone and Bones; Dinoprostone; Fibroblast Growth Factor 9; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibronectins; Humans; Interleukin-6; Muscle, Skeletal; Myostatin; Osteocalcin; Paracrine Communication; RANK Ligand; Somatomedins; Wnt1 Protein; Wnt3A Protein
PubMed: 32519283
DOI: 10.1007/s11914-020-00602-6 -
Stem Cell Research & Therapy Nov 2019The inflammation and regeneration process may be accompanied by the shift in the M1/M2 polarization of macrophages to adapt to extracellular signals. How the macrophages...
BACKGROUND
The inflammation and regeneration process may be accompanied by the shift in the M1/M2 polarization of macrophages to adapt to extracellular signals. How the macrophages responded to the altered immunological environment in the periodontal niche after stem cell transplantation has never been explored. The purpose of present study is to investigate whether M1/M2 polarization of macrophages participated in the tissue homeostasis and wound healing during periodontal ligament stem cell (PDLSC)-based periodontal regeneration.
METHODS
A rat periodontal defect model was utilized to observe the regeneration process in the PDLSC transplantation-enhanced periodontal repair. Dynamic changes in the markers of M1/M2 macrophages were observed on days 3, 7, and 21 post surgery. In addition, the outcome of regeneration was analyzed on day 21 after surgery. To further investigate the effect of PDLSCs on macrophage polarization, the conditioned medium of PDLSCs was utilized to treat M0, M1, and M2 macrophages for 24 h; markers of M1/M2 polarization were evaluated in macrophages.
RESULTS
Elevated bone volume and average thickness of bone trabecular was observed in the PDLSC-treated group by micro-computed tomography on day 21. In addition, enhanced periodontal regeneration was observed in the PDLSC-treated group with cementum-like structure regeneration and collagen fiber formation, which inserted into the newly formed cementum. On day 3, PDLSC transplantation increased IL-10 level in the periodontal tissue, while decreased TNF-α in the early stage of periodontal regeneration. On day 7, enhanced CD163+ cell infiltration and heightened expression of markers of M2 macrophages were observed. Furthermore, conditioned medium from PDLSC culture induced macrophage polarization towards the anti-inflammatory phenotype by downregulating TNF-α and upregulating IL-10, Arg-1, and CD163 in vitro.
CONCLUSIONS
PDLSCs could induce macrophage polarization towards the M2 phenotype, and the shift in the polarization towards M2 macrophages in the early stage of tissue repair contributed to the enhanced periodontal regeneration after stem cell transplantation. Therefore, signals from the transplanted PDLSCs might alter the immune microenvironment to enhance periodontal regeneration.
Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cell Count; Cell Polarity; Cells, Cultured; Culture Media, Conditioned; Cytokines; Interferon-gamma; Interleukin-4; Lipopolysaccharides; Macrophages; Male; Paracrine Communication; Periodontal Ligament; Rats, Sprague-Dawley; Receptors, Cell Surface; Regeneration; Stem Cells
PubMed: 31730019
DOI: 10.1186/s13287-019-1409-4 -
The Journal of Experimental Medicine Feb 2021Macrophages help defend the host against Mycobacterium tuberculosis (Mtb), the major cause of tuberculosis (TB). Once phagocytized, Mtb resists killing by macrophages,...
Macrophages help defend the host against Mycobacterium tuberculosis (Mtb), the major cause of tuberculosis (TB). Once phagocytized, Mtb resists killing by macrophages, replicates inside them, and leads to their death, releasing Mtb that can infect other cells. We found that the death of Mtb-infected mouse macrophages in vitro does not appear to proceed by a currently known pathway. Through genome-wide CRISPR-Cas9 screening, we identified a critical role for autocrine or paracrine signaling by macrophage-derived type I IFNs in the death of Mtb-infected macrophages in vitro, and blockade of type I IFN signaling augmented the effect of rifampin, a first-line TB drug, in Mtb-infected mice. Further definition of the pathway of type I IFN-mediated macrophage death may allow for host-directed therapy of TB that is more selective than systemic blockade of type I IFN signaling.
Topics: Animals; Autocrine Communication; CRISPR-Cas Systems; Cell Death; Cell Line; HEK293 Cells; Humans; Interferon Type I; Macrophages; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Paracrine Communication; RAW 264.7 Cells; Rifampin; Signal Transduction; Tuberculosis
PubMed: 33125053
DOI: 10.1084/jem.20200887 -
Cell Jul 2021A fraction of mature T cells can be activated by peripheral self-antigens, potentially eliciting host autoimmunity. We investigated homeostatic control of...
A fraction of mature T cells can be activated by peripheral self-antigens, potentially eliciting host autoimmunity. We investigated homeostatic control of self-activated T cells within unperturbed tissue environments by combining high-resolution multiplexed and volumetric imaging with computational modeling. In lymph nodes, self-activated T cells produced interleukin (IL)-2, which enhanced local regulatory T cell (Treg) proliferation and inhibitory functionality. The resulting micro-domains reciprocally constrained inputs required for damaging effector responses, including CD28 co-stimulation and IL-2 signaling, constituting a negative feedback circuit. Due to these local constraints, self-activated T cells underwent transient clonal expansion, followed by rapid death ("pruning"). Computational simulations and experimental manipulations revealed the feedback machinery's quantitative limits: modest reductions in Treg micro-domain density or functionality produced non-linear breakdowns in control, enabling self-activated T cells to subvert pruning. This fine-tuned, paracrine feedback process not only enforces immune homeostasis but also establishes a sharp boundary between autoimmune and host-protective T cell responses.
Topics: Animals; Autoantigens; CD4-Positive T-Lymphocytes; Cell Proliferation; Feedback, Physiological; Homeostasis; Interleukin-2; Lymphocyte Activation; Membrane Microdomains; Mice, Inbred C57BL; Models, Immunological; Paracrine Communication; Signal Transduction; T-Lymphocytes, Regulatory; Mice
PubMed: 34157301
DOI: 10.1016/j.cell.2021.05.028 -
The Journal of Investigative Dermatology Aug 2022Androgenetic alopecia (AGA), also known as male pattern baldness, is associated with androgen and androgen receptor (AR) signaling; however, the pathogenesis of AGA...
Androgenetic alopecia (AGA), also known as male pattern baldness, is associated with androgen and androgen receptor (AR) signaling; however, the pathogenesis of AGA remains largely unknown. In this study, we show that nuclear localization of AR is elevated in the dermal papilla (DP) of balding scalp in patients with AGA. Transcriptome analysis identifies microvascular abnormalities in the DP of balding scalp compared with nonbalding scalp of patients with AGA. We provide further evidence that blood vessels regress in the DP of balding scalp at the early stage of hair follicle miniaturization in AGA development. Consistently, we find that microvascular vessels accumulate around the DP on anagen initiation, and angiogenesis is required for hair regeneration in mice. Mechanistically, we show that AR-mediated paracrine signaling, mainly TGFβ signaling, from DP cells induces apoptosis of microvascular endothelial cells in the DP of balding scalp of AGA. These findings define a role of AR-mediated regression of blood vessels in DP in AGA and support the notion that early anti-AR treatment is better than late treatment.
Topics: Alopecia; Androgens; Animals; Endothelial Cells; Hair Follicle; Male; Mice; Paracrine Communication; Receptors, Androgen
PubMed: 35033537
DOI: 10.1016/j.jid.2022.01.003 -
Journal of Experimental & Clinical... Feb 2022Perineural invasion (PNI) and autophagy are two common features in the tumor microenvironment of pancreatic cancer (PanCa) and have a negative effect on prognosis....
BACKGROUND
Perineural invasion (PNI) and autophagy are two common features in the tumor microenvironment of pancreatic cancer (PanCa) and have a negative effect on prognosis. Potential mediator cells and the molecular mechanism underlying their relationships need to be fully elucidated.
METHODS
To investigate the autophagy of Schwann cells (SCs) in PNI, we reproduced the microenvironment of PNI by collecting clinical PNI tissue, performing sciatic nerve injection of nude mice with cancer cells and establishing a Dorsal root ganglion (DRG) coculture system with cancer cell lines. Autophagy was detected by IHC, IF, transmission electron microscopy (TEM) and western blotting assays. Apoptosis was detected by IF, TEM and western blotting. NGF targeting molecular RO 08-2750(RO) and the autophagy inhibitor Chloroquine (CQ) were utilized to evaluate the effect on autophagy and apoptosis in SCs and PanCa cells in PNI samples.
RESULTS
SC autophagy is activated in PNI by paracrine NGF from PanCa cells. Autophagy-activated Schwann cells promote PNI through a) enhanced migration and axon guidance toward PanCa cells and b) increased chemoattraction to PanCa cells. The NGF-targeting reagent RO and autophagy inhibitor CQ inhibited Schwann cell autophagic flux and induced Schwann cell apoptosis. Moreover, RO and CQ could induce PanCa cell apoptosis and showed good therapeutic effects in the PNI model.
CONCLUSIONS
PanCa cells can induce autophagy in SCs through paracrine pathways such as the NGF/ATG7 pathway. Autophagic SCs exert a "nerve-repair like effect", induce a high level of autophagy of cancer cells, provide a "beacon" for the invasion of cancer cells to nerve fibers, and induce directional growth of cancer cells. Targeting NGF and autophagy for PNI treatment can block nerve infiltration and is expected to provide new directions and an experimental basis for the research and treatment of nerve infiltration in pancreatic cancer.
Topics: Adenocarcinoma; Animals; Autophagy; Carcinoma, Pancreatic Ductal; Disease Models, Animal; Female; Humans; Mice; Neoplasm Invasiveness; Nerve Growth Factor; Paracrine Communication; Rats; Schwann Cells; Transfection; Tumor Microenvironment
PubMed: 35109895
DOI: 10.1186/s13046-021-02198-w -
Cell Reports Mar 2020Muscle regeneration relies on the regulation of muscle stem cells (MuSCs) through paracrine signaling interactions. We analyzed muscle regeneration in mice using...
Muscle regeneration relies on the regulation of muscle stem cells (MuSCs) through paracrine signaling interactions. We analyzed muscle regeneration in mice using single-cell RNA sequencing (scRNA-seq) and generated over 34,000 single-cell transcriptomes spanning four time-points. We identified 15 distinct cell types including heterogenous populations of muscle stem and progenitor cells. We resolved a hierarchical map of these myogenic cells by trajectory inference and observed stage-specific regulatory programs within this continuum. Through ligand-receptor interaction analysis, we identified over 100 candidate regeneration-associated paracrine communication pairs between MuSCs and non-myogenic cells. We show that myogenic stem/progenitor cells exhibit heterogeneous expression of multiple Syndecan proteins in cycling myogenic cells, suggesting that Syndecans may coordinate myogenic fate regulation. We performed ligand stimulation in vitro and confirmed that three paracrine factors (FGF2, TGFβ1, and RSPO3) regulate myogenic cell proliferation in a Syndecan-dependent manner. Our study provides a scRNA-seq reference resource to investigate cell communication interactions in muscle regeneration.
Topics: Adipogenesis; Animals; Cell Communication; Cell Proliferation; Gene Expression Regulation; Ligands; Mice, Inbred C57BL; Models, Biological; Muscle Development; Muscle, Skeletal; Paracrine Communication; RNA-Seq; Receptors, Cell Surface; Regeneration; Signal Transduction; Single-Cell Analysis; Stem Cells; Syndecans
PubMed: 32160558
DOI: 10.1016/j.celrep.2020.02.067