Cancer cell migration and invasion underlie metastatic dissemination, one of the major problems in cancer. Tumour cells exhibit a striking variety of invasion strategies. Importantly, cancer cells ...can switch between invasion modes in order to cope with challenging environments. This ability to switch migratory modes or plasticity highlights the challenges behind antimetastasis therapy design. In this Review, we present current knowledge on different tumour invasion strategies, the determinants controlling plasticity and arising therapeutic opportunities. We propose that targeting master regulators controlling plasticity is needed to hinder tumour dissemination and metastasis.
This Review gives an overview of cell migration mechanisms and describes the different individual and collective modes of invasion, the plasticity that enables cancer cells to switch between modes, and the determinants of this plasticity. Therapeutic challenges arising from migratory plasticity and the potential targets that could block completely cancer cell invasion are also discussed.
TGFΒ-induced transcription in cancer Cantelli, Gaia; Crosas-Molist, Eva; Georgouli, Mirella ...
Seminars in cancer biology,
02/2017, Letnik:
42
Journal Article
Recenzirano
Odprti dostop
Abstract The Transforming Growth Factor-beta (TGFβ) pathway mediates a broad spectrum of cellular processes and is involved in several diseases, including cancer. TGFβ has a dual role in tumours, ...acting as a tumour suppressor in the early phase of tumorigenesis and as a tumour promoter in more advanced stages. In this review, we discuss the effects of TGFβ-driven transcription on all stages of tumour progression, with special focus on lung cancer. Since some TGFβ target genes are specifically involved in promoting metastasis, we speculate that these genes might be good targets to block tumour progression without compromising the tumour suppressor effects of the TGFβ pathway.
Abnormal cell migration and invasion underlie metastatic dissemination, one of the major challenges for cancer treatment. Melanoma is one of the deadliest and most aggressive forms of skin cancer due ...in part to its migratory and metastatic potential. Cancer cells use a variety of migratory strategies regulated by cytoskeletal remodelling. In particular, we discuss the importance of amoeboid invasive melanoma strategies, since they have been identified at the edge of human melanomas. We hypothesize that the presence of amoeboid melanoma cells will favour tumor progression since they are invasive and metastatic; they support immunosuppression; they harbour cancer stem cell properties and they are involved in therapy resistance. The Rho‐ROCK‐Myosin II pathway is key to maintain amoeboid melanoma invasion but this pathway is further regulated by pro‐tumorigenic/pro‐metastatic/pro‐survival signalling pathways such as JAK‐STAT3, TGFβ‐SMAD, NF‐κB, Wnt11/5‐FDZ7 and BRAFV600E‐MEK‐ERK. These pathways support amoeboid behaviour and are actionable in the clinic. After melanoma wide surgical margin removal, we propose that possible remaining melanoma cells should be eradicated using anti‐amoeboid therapies.
Non‐melanoma skin cancer (NMSC) is characterized by a strong desmoplastic reaction, largely responsible for cancer aggressiveness. Within the tumour microenvironment, cancer‐associated fibroblasts ...(CAFs) play a key role in tumour progression, secretion of extracellular matrix proteins and recruitment of immunosuppressive cells. However, pathways involved in acquisition of CAF phenotype remain unclear. In this issue of EMBO Molecular Medicine, Cangkrama et al describe a new mechanism of fibroblast activation in squamous cell carcinoma. Cancer cell‐secreted activin A induces a tumour‐promoting phenotype in the fibroblast compartment, with distinct properties compared to TGF‐β‐activated fibroblasts. Activin A reprograms fibroblasts through transcriptional regulation of mDia2 and reduction of nuclear p53, which favours CAF marker expression, and increases tumour growth and migration. Inhibition of this pathway shows promising results in different models and could offer a new therapeutic strategy in NMSC.
V. Sanz‐Moreno and R. Samain discuss a new mechanism of fibroblast activation mediated by squamous cell carcinoma‐secreted Activin A, and whose inhibition shows promising results in non‐melanoma skin cancer (Cangkrama et al, this issue of EMBO Mol Med).
p21-Activated kinase 4 (PAK4), a serine/threonine kinase, is purported to localize to podosomes: transient adhesive structures that degrade the extracellular matrix to facilitate rapid myeloid cell ...migration. We find that treatment of transforming growth factor β (TGF-β)-differentiated monocytic (THP-1) cells with a PAK4-targeted inhibitor significantly reduces podosome formation and induces the formation of focal adhesions. This switch in adhesions confers a diminution of matrix degradation and reduced cell migration. Furthermore, reduced PAK4 expression causes a significant reduction in podosome number that cannot be rescued by kinase-dead PAK4, supporting a kinase-dependent role. Concomitant with PAK4 depletion, phosphorylation of Akt is perturbed, whereas a specific phospho-Akt signal is detected within the podosomes. Using superresolution analysis, we find that PAK4 specifically localizes in the podosome ring, nearer to the actin core than other ring proteins. We propose PAK4 kinase activity intersects with the Akt pathway at the podosome ring:core interface to drive regulation of macrophage podosome turnover.
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•PAK4 kinase activity is crucial to macrophage podosome dynamics•Podosome loss due to PAK4 suppression reduces migration speed and degradation•PAK4 localizes to the podosome ring where it interacts with vinculin and paxillin
The differential role of PAK family proteins in podosome function has not been previously evaluated. Foxall et al. demonstrate that PAK4 rather than PAK1 plays a pivotal role and use super resolution microscopy to position PAK4 at the podosome ring:core interface.
Summary
Metastatic cutaneous melanoma accounts for the majority of skin cancer deaths due to its aggressiveness and high resistance to current therapies. To efficiently metastasize, invasive melanoma ...cells need to change their cytoskeletal organization and alter contacts with the extracellular matrix and the surrounding stromal cells. Melanoma cells can use different migratory strategies depending on varying environments to exit the primary tumour mass and invade surrounding and later distant tissues. In this review, we have focused on tumour cell plasticity or the interconvertibility that melanoma cells have as one of the factors that contribute to melanoma metastasis. This has been an area of very intense research in the last 5 yr yielding a vast number of findings. We have therefore reviewed all the possible clinical opportunities that this new knowledge offers to both stratify and treat cutaneous malignant melanoma patients.
Due to the use of intra-vital imaging techniques and assays for cell migration into 3D matrices there has recently been much interest in different modes of tumour cell migration. Individually moving ...tumour cells can move either in an elongated-protrusive manner or in rounded, so-called ‘amoeboid’ modes. This review summarises ongoing efforts to delineate the cell signalling pathways that underlie these different forms of movement.
Rho GTPases are a family of small G proteins that regulate a wide array of cellular processes related to their key roles controlling the cytoskeleton. Cancer is a multistep disease caused by the ...accumulation of genetic mutations and epigenetic alterations, from the initial stages of cancer development when cells in normal tissues undergo transformation, to the acquisition of invasive and metastatic traits, responsible for a large number of cancer related deaths. In this review, we discuss the role of Rho GTPase signaling in cancer in every step of disease progression. Rho GTPases contribute to tumor initiation and progression, by regulating proliferation and apoptosis, but also metabolism, senescence, and cancer cell stemness. Rho GTPases play a major role in cell migration and in the metastatic process. They are also involved in interactions with the tumor microenvironment and regulate inflammation, contributing to cancer progression. After years of intensive research, we highlight the importance of relevant models in the Rho GTPase field, and we reflect on the therapeutic opportunities arising for cancer patients.
Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways ...through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α-ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment.
Tumor cells exhibit two different modes of individual cell movement. Mesenchymal-type movement is characterized by an elongated cellular morphology and requires extracellular proteolysis. In amoeboid ...movement, cells have a rounded morphology, are less dependent on proteases, and require high Rho-kinase signaling to drive elevated levels of actomyosin contractility. These two modes of cell movement are interconvertible. We show that mesenchymal-type movement in melanoma cells is driven by activation of the GTPase Rac through a complex containing NEDD9, a recently identified melanoma metastasis gene, and DOCK3, a Rac guanine nucleotide exchange factor. Rac signals through WAVE2 to direct mesenchymal movement and suppress amoeboid movement through decreasing actomyosin contractility. Conversely, in amoeboid movement, Rho-kinase signaling activates a Rac GAP, ARHGAP22, that suppresses mesenchymal movement by inactivating Rac. We demonstrate tight interplay between Rho and Rac in determining different modes of tumor cell movement, revealing how tumor cells switch between different modes of movement.
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