Mesenchymal stem cells (MSCs) are multipotent tissue stem cells that differentiate into a number of mesodermal tissue types, including osteoblasts, adipocytes, chondrocytes and myofibroblasts. MSCs ...were originally identified in the bone marrow (BM) of humans and other mammals, but recent studies have shown that they are multilineage progenitors in various adult organs and tissues. MSCs that localize at perivascular sites function to rapidly respond to external stimuli and coordinate with the vascular and immune systems to accomplish the wound healing process. Cancer, considered as wounds that never heal, is also accompanied by changes in MSCs that parallels the wound healing response. MSCs are now recognized as key players at distinct steps of tumorigenesis. In this review, we provide an overview of the function of MSCs in wound healing and cancer progression with the goal of providing insight into the development of novel MSC-manipulating strategies for clinical cancer treatment.
Signaling through RAS/MAP kinase pathway is central to biology. ERK has long been perceived as the only substrate for MEK. Here, we report that HSF1, the master regulator of the proteotoxic stress ...response, is a new MEK substrate. Beyond mediating cell-environment interactions, the MEK-HSF1 regulation impacts malignancy. In tumor cells, MEK blockade inactivates HSF1 and thereby provokes proteomic chaos, presented as protein destabilization, aggregation, and, strikingly, amyloidogenesis. Unlike their non-transformed counterparts, tumor cells are particularly susceptible to proteomic perturbation and amyloid induction. Amyloidogenesis is tumor suppressive, reducing in vivo melanoma growth and contributing to the potent anti-neoplastic effects of proteotoxic stressors. Our findings unveil a key biological function of the oncogenic RAS-MEK signaling in guarding proteostasis and suppressing amyloidogenesis. Thus, proteomic instability is an intrinsic feature of malignant state, and disrupting the fragile tumor proteostasis to promote amyloidogenesis may be a feasible therapeutic strategy.
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•MEK physically interacts with and phosphorylates HSF1 at Ser326•MEK mobilizes and ERK suppresses the HSF1-mediated proteotoxic stress response•MEK inhibition disrupts proteostasis and provokes tumor-suppressive amyloidogenesis•Malignancy is susceptible to proteomic perturbation and subsequent amyloidogenesis
The identification of HSF1 as a new substrate for MEK reveals that the RAS/MAP kinase pathway regulates proteostasis in normal cells and that it can be targeted to promote proteomic instability and amyloidogenesis in cancer cells.
Rodent models for human diseases contribute significantly to understanding human physiology and pathophysiology. However, given the accelerating pace of drug development, there is a crucial need for ...in vivo preclinical models of human biology and pathology. The humanized mouse is one tool to bridge the gap between traditional animal models and the clinic. The development of immunodeficient mouse strains with high-level engraftment of normal and diseased human immune/hematopoietic cells has made in vivo functional characterization possible. As a patient-derived xenograft (PDX) model, humanized mice functionally correlate putative mechanisms with in vivo behavior and help to reveal pathogenic mechanisms. Combined with single-cell genomics, humanized mice can facilitate functional precision medicine such as risk stratification and individually optimized therapeutic approaches.
New generations of humanized mice replicate much of the complexity and heterogeneity of both normal and malignant human hematopoiesis.Humanized mice allow in vivo characterization of the engraftment and differentiation capacities of hematopoietic stem/progenitor cell subpopulations, as well as the functional discrimination of normal and malignant stem cells.Humanized mice can support a functional correlation of genomic data with the in vivo characteristics of hematopoietic cells. Combined with single-cell genomics, the genetic heterogeneity within subpopulations of normal or malignant human hematopoietic cells can be linked to in vivo functions and can reveal pathogenetic mechanisms.
Humanized mice in translational biomedical research Shultz, Leonard D; Ishikawa, Fumihiko; Greiner, Dale L
Nature Reviews: Immunology,
200702, 2007-Feb, 2007-2-00, 20070201, Letnik:
7, Številka:
2
Journal Article
Recenzirano
The culmination of decades of research on humanized mice is leading to advances in our understanding of human haematopoiesis, innate and adaptive immunity, autoimmunity, infectious diseases, cancer ...biology and regenerative medicine. In this Review, we discuss the development of these new generations of humanized mice, how they will facilitate translational research in several biomedical disciplines and approaches to overcome the remaining limitations of these models.
Abstract
The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have ...been reported. In this study, using mouse models of breast cancer, we demonstrate that the metastasis-modulating effects of neutrophils are dictated by the status of host natural killer (NK) cells. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. In contrast, in NK cell-competent mice, neutrophils facilitate metastatic colonization in the same tumor models. In an ex vivo neutrophil-NK cell-tumor cell tri-cell co-culture system, neutrophils are shown to potentially suppress the tumoricidal activity of NK cells, while neutrophils themselves are tumoricidal. Intriguingly, these two modulatory effects by neutrophils are both mediated by reactive oxygen species. Collectively, the absence or presence of NK cells, governs the net tumor-modulatory effects of neutrophils.
Primary tumors are drivers of pre-metastatic niche formation, but the coordination by the secondary organ toward metastatic dissemination is underappreciated. Here, by single-cell RNA sequencing and ...immunofluorescence, we identified a population of cyclooxygenase 2 (COX-2)-expressing adventitial fibroblasts that remodeled the lung immune microenvironment. At steady state, fibroblasts in the lungs produced prostaglandin E2 (PGE2), which drove dysfunctional dendritic cells (DCs) and suppressive monocytes. This lung-intrinsic stromal program was propagated by tumor-associated inflammation, particularly the pro-inflammatory cytokine interleukin-1β, supporting a pre-metastatic niche. Genetic ablation of Ptgs2 (encoding COX-2) in fibroblasts was sufficient to reverse the immune-suppressive phenotypes of lung-resident myeloid cells, resulting in heightened immune activation and diminished lung metastasis in multiple breast cancer models. Moreover, the anti-metastatic activity of DC-based therapy and PD-1 blockade was improved by fibroblast-specific Ptgs2 deletion or dual inhibition of PGE2 receptors EP2 and EP4. Collectively, lung-resident fibroblasts reshape the local immune landscape to facilitate breast cancer metastasis.
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•Lung metastasis is promoted by COX-2+ lung adventitial fibroblasts (AdvFs)•At steady state, COX-2+ AdvFs drive myeloid cell dysfunction or immunosuppression•Tumor-driven IL-1β reinforces myeloid cell reprogramming by COX-2+ lung AdvFs•Targeting PGE2 signaling improves the efficacy of DC vaccine or anti-PD-1 treatment
Improved understanding of how the lung stroma contributes to the development of an immunosuppressive pre-metastatic niche could potentiate new anti-cancer treatments. Here, Gong et al. identify COX-2+ lung fibroblasts that reprogram diverse myeloid cells to be dysfunctional or immunosuppressive. Targeting COX-2+ AdvFs reduced lung metastasis and improved efficacy of immunotherapeutics.
While the distant organ environment is known to support metastasis of primary tumors, its metabolic roles in this process remain underdetermined. Here, in breast cancer models, we found lung-resident ...mesenchymal cells (MCs) accumulating neutral lipids at the pre-metastatic stage. This was partially mediated by interleukin-1β (IL-1β)-induced hypoxia-inducible lipid droplet-associated (HILPDA) that subsequently represses adipose triglyceride lipase (ATGL) activity in lung MCs. MC-specific ablation of the ATGL or HILPDA genes in mice reinforced and reduced lung metastasis of breast cancer respectively, suggesting a metastasis-promoting effect of lipid-laden MCs. Mechanistically, lipid-laden MCs transported their lipids to tumor cells and natural killer (NK) cells via exosome-like vesicles, leading to heightened tumor cell survival and proliferation and NK cell dysfunction. Blockage of IL-1β, which was effective singly, improved the efficacy of adoptive NK cell immunotherapy in mitigating lung metastasis. Collectively, lung MCs metabolically regulate tumor cells and anti-tumor immunity to facilitate breast cancer lung metastasis.
Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into the mechanisms underlying cancer immunotherapy. To this ...end, nonobese diabetic (NOD).Cg‐PrkdcscidIL2rgtm1Wjl/Sz (null; NSG) mice were transplanted with human (h)CD34+hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems humanized NSG (HuNSG). HuNSG mice received human leukocyte antigen partially matched tumor implants from patient‐ derived xenografts PDX; non‐small cell lung cancer (NSCLC), sarcoma, bladder cancer, and triple‐negative breast cancer (TNBC) or from a TNBC cell line‐derived xenograft (CDX). Tumor growth curves were similar in HuNSG compared with nonhuman immune‐engrafted NSG mice. Treatment with pembrolizumab, which targets programmed cell death protein 1, produced significant growth inhibition in both CDX and PDX tumors in HuNSG but not in NSG mice. Finally, inhibition of tumor growth was dependent on hCD8+T cells, as demonstrated by antibody‐mediated depletion. Thus, tumor‐bearing HuNSG mice may represent an important, new model for preclinical immunotherapy research.—Wang, M., Yao, L.‐C., Cheng, M., Cai, D., Martinek, J., Pan, C.‐X., Shi, W., Ma, A.‐H., De Vere White, R. W., Airhart, S., Liu, E. T., Banchereau, J., Brehm, M. A., Greiner, D. L., Shultz, L. D., Palucka, K., Keck, J. G. Humanized mice in studying efficacy and mechanisms of PD‐1‐targeted cancer immunotherapy. FASEB J. 32,1537‐1549 (2018). www.fasebj.org
A systematic characterization of the genetic alterations driving ALCLs has not been performed. By integrating massive sequencing strategies, we provide a comprehensive characterization of driver ...genetic alterations (somatic point mutations, copy number alterations, and gene fusions) in ALK− ALCLs. We identified activating mutations of JAK1 and/or STAT3 genes in ∼20% of 88 ALK− ALCLs and demonstrated that 38% of systemic ALK− ALCLs displayed double lesions. Recurrent chimeras combining a transcription factor (NFkB2 or NCOR2) with a tyrosine kinase (ROS1 or TYK2) were also discovered in WT JAK1/STAT3 ALK− ALCL. All these aberrations lead to the constitutive activation of the JAK/STAT3 pathway, which was proved oncogenic. Consistently, JAK/STAT3 pathway inhibition impaired cell growth in vitro and in vivo.
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•Co-occurring somatic mutations of JAK1 and STAT3 promote oncogenesis•Novel chimera fuse transcription/repressor domains to tyrosine kinases (TKs)•Dual functional TK fusions are oncogenic and mediate STAT3 transformation•JAK/STAT3 inhibitors have therapeutic efficacy in pre-clinical ALCL models
Crescenzo et al. provide a comprehensive characterization of driver genetic alterations in ALK− anaplastic large cell lymphomas (ALCLs) and uncover mechanisms leading to the constitutive activation of STAT3 in ALK− ALCL. JAK/STAT3 inhibitors have therapeutic efficacy in pre-clinical ALCL models.
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