Fibroblast-Derived STC-1 Modulates Tumor-Associated Macrophages and Lung Adenocarcinoma Development

Kamata, Tamihiro; So, Tsz Y; Ahmed, Qasim; Giblett, Susan; Patel, Bipin; Luo, Juan; Reddel, Roger R.; Pritchard, Catrin

doi:10.1016/j.celrep.2020.107802

Cited by 24 publications

(32 citation statements)

References 77 publications

(107 reference statements)

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“… 339 The CAF–TAM interaction was also regulated by pleiotropic glycoprotein stanniocalcin-1, which was secreted by CAFs and partially suppressed TAM differentiation. 340 In colorectal cancer, CAFs could attract monocytes via IL-8/CXCR2 pathway to induce their polarization. 341 Thus, CAFs play crucial roles in shaping the immunosuppressive TME by educating TAMs to induce a protumor phenotype, and methods for reversing CAF-mediated immunosuppression in TAM-targeted therapeutics need to be considered.…”

Section: Immunotheray Driven By Cafsmentioning

confidence: 99%

Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer

Yang

Liu

et al. 2021

Sig Transduct Target Ther

329

249

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To flourish, cancers greatly depend on their surrounding tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in TME are critical for cancer occurrence and progression because of their versatile roles in extracellular matrix remodeling, maintenance of stemness, blood vessel formation, modulation of tumor metabolism, immune response, and promotion of cancer cell proliferation, migration, invasion, and therapeutic resistance. CAFs are highly heterogeneous stromal cells and their crosstalk with cancer cells is mediated by a complex and intricate signaling network consisting of transforming growth factor-beta, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin, mitogen-activated protein kinase, Wnt, Janus kinase/signal transducers and activators of transcription, epidermal growth factor receptor, Hippo, and nuclear factor kappa-light-chain-enhancer of activated B cells, etc., signaling pathways. These signals in CAFs exhibit their own special characteristics during the cancer progression and have the potential to be targeted for anticancer therapy. Therefore, a comprehensive understanding of these signaling cascades in interactions between cancer cells and CAFs is necessary to fully realize the pivotal roles of CAFs in cancers. Herein, in this review, we will summarize the enormous amounts of findings on the signals mediating crosstalk of CAFs with cancer cells and its related targets or trials. Further, we hypothesize three potential targeting strategies, including, namely, epithelial–mesenchymal common targets, sequential target perturbation, and crosstalk-directed signaling targets, paving the way for CAF-directed or host cell-directed antitumor therapy.

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Section: Immunotheray Driven By Cafsmentioning

confidence: 99%

Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer

Yang

Liu

et al. 2021

Sig Transduct Target Ther

329

249

View full text Add to dashboard Cite

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“…56 Alternative depleting agents have also been successfully investigated in MPM models, 54 71 while our own work has also identified the fibroblast-derived secreted protein STC1 as an additional regulator of TAM differentiation in lung adenocarcinoma. 72 By contrast, reprogramming strategies attempt to stimulate TAMs to repress their protumor functions and switch to a phagocytic role. A reprogramming function of CSF-1R inhibition has been proposed in glioma, which results in downregulation of M2-like markers, 73 possibly by diverting classical monocyte maturation from the CSF-1 to the CSF-2 pathway.…”

Section: Targeting Tams In Novel Mpm Immunotherapiesmentioning

confidence: 99%

Matter of TIME: the tumor-immune microenvironment of mesothelioma and implications for checkpoint blockade efficacy

Harber

Kamata

Pritchard

et al. 2021

J Immunother Cancer

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Malignant pleural mesothelioma (MPM) is an incurable cancer with a dismal prognosis and few effective treatment options. Nonetheless, recent positive phase III trial results for immune checkpoint blockade (ICB) in MPM herald a new dawn in the fight to advance effective treatments for this cancer. Tumor mutation burden (TMB) has been widely reported to predict ICB in other cancers, but MPM is considered a low-TMB tumor. Similarly, tumor programmed death-ligand 1 (PD-L1) expression has not been proven predictive in phase III clinical trials in MPM. Consequently, the precise mechanisms that determine response to immunotherapy in this cancer remain unknown. The present review therefore aimed to synthesize our current understanding of the tumor immune microenvironment in MPM and reflects on how specific cellular features might impact immunotherapy responses or lead to resistance. This approach will inform stratified approaches to therapy and advance immunotherapy combinations in MPM to improve clinical outcomes further.

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“…TAM-like F4/80+ cells (Kamata et al, 2020;Franklin et al, 2014) were the sole cell populations in the stroma significantly decreased by atorvastatin when compared as relative percentages (Fig. 3D) suggesting that, as with the BRAF V600E model, these are the primary cell targets of atorvastatin.…”

Section: Disease Models and Mechanisms • Dmm • Accepted Manuscriptmentioning

confidence: 77%

“…1C). Quantitative analysis of CD11c+ stromal immature macrophage lineage cells (IMCs) and surfactant protein-C (SPC)+ adenoma cells using flow cytometry (Kamata et al, 2015;Kamata et al, 2020) confirmed that both cell types were robustly decreased by atorvastatin treatment (Fig. 1D).…”

Section: Atorvastatin Inhibits Braf V600e -Driven Lung Adenoma Developmentmentioning

confidence: 82%

Statins mediate anti- and pro-tumourigenic functions by remodelling the tumour microenvironment

Kamata

Dujaily

Alhamad

et al. 2022

Disease Models &Amp; Mechanisms

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Anti-cancer properties of statins are controversial, and possibly context-dependent. Recent pathology/epidemiology studies of human lung adenocarcinoma showed reduced protumourigenic macrophages associated with a shift to lower grade tumours amongst statin users but, paradoxically, worse survival compared to non-users. To investigate the mechanisms involved, we have characterised mouse lung adenoma/adenocarcinoma models treated with atorvastatin. Here we show that atorvastatin suppresses premalignant disease by inhibiting the recruitment of protumourigenic macrophages to the tumour microenvironment, manifested in part by suppression of Rac-mediated CCR1 ligand secretion. However, prolonged atorvastatin treatment leads to drug resistance and progression of lung adenomas into invasive disease. Pathological progression is not driven by acquisition of additional driver mutations or immunoediting/evasion but is associated with stromal changes including the development of desmoplastic stroma containing Gr1+ myeloid cells and tertiary lymphoid structures (TLS). These findings show that any chemopreventive functions of atorvastatin in lung adenocarcinoma are overridden by stromal remodelling in the long term, thus providing mechanistic insight into the poor survival of lung adenocarcinoma patients with statin use.

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Fibroblast-Derived STC-1 Modulates Tumor-Associated Macrophages and Lung Adenocarcinoma Development

Cited by 24 publications

References 77 publications

Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer

Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer

Matter of TIME: the tumor-immune microenvironment of mesothelioma and implications for checkpoint blockade efficacy

Statins mediate anti- and pro-tumourigenic functions by remodelling the tumour microenvironment

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