TGF-β-Induced Transcription Sustains Amoeboid Melanoma Migration and Dissemination

Abstract

SummaryCell migration underlies metastatic dissemination of cancer cells, and fast “amoeboid” migration in the invasive fronts of tumors is controlled by high levels of actomyosin contractility. How amoeboid migration is regulated by extracellular signals and sustained over time by transcriptional changes is not fully understood. Transforming growth factor β (TGF-β) is well known to promote epithelial-to-mesenchymal transition (EMT) and contribute to metastasis, but melanocytes are neural crest derivatives that have undergone EMT during embryonic development. Surprisingly, we find that in melanoma, TGF-β promotes amoeboid features such as cell rounding, membrane blebbing, high levels of contractility, and increased invasion. Using genome-wide transcriptomics, we find that amoeboid melanoma cells are enriched in a TGF-β-driven signature. We observe that downstream of TGF-β, SMAD2 and its adaptor CITED1 control amoeboid behavior by regulating the expression of key genes that activate contractile forces. Moreover, CITED1 is highly upregulated during melanoma progression, and its high expression is associated with poor prognosis. CITED1 is coupled to a contractile-rounded, amoeboid phenotype in a panel of 16 melanoma cell lines, in mouse melanoma xenografts, and in 47 human melanoma patients. Its expression is also enriched in the invasive fronts of lesions. Functionally, we show how the TGF-β-SMAD2-CITED1 axis promotes different steps associated with progression: melanoma detachment from keratinocytes, 2D and 3D migration, attachment to endothelial cells, and in vivo lung metastatic initial colonization and outgrowth. We propose a novel mechanism by which TGF-β-induced transcription sustains actomyosin force in melanoma cells and thereby promotes melanoma progression independently of EMT.

RAB27A promotes melanoma cell invasion and metastasis via regulation of pro‐invasive exosomes

“…Proteins involved in modulating the extracellular matrix may also be involved in the pro‐invasive action of RAB27A‐replete exosomes, as gene ontology terms related to “extracellular matrix” and “extracellular matrix disassembly” were enriched in the proteomic analysis. For example, BMP‐1 is a metalloprotease that has been linked to cancer metastasis and TGF‐β activation; TGF‐β has a known role in melanoma migration and dissemination …”

“…For example, BMP-1 is a metalloprotease that has been linked to cancer metastasis and TGF-β activation 50 ; TGF-β has a known role in melanoma migration and dissemination. 51 RAB GTPases are increasingly being implicated in cancer progression in many different cancer types. 52 Most notably, RAB7 has been linked to a lineage-specific tumor dependency in melanoma.…”

Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma

“…Though we, and others, can detect both physical and functional interactions between TBK1, LATS, and YAP1, we have not yet defined the mechanism by which TBK1/IKKε participate in Hippo pathway regulation. However, compelling observations in drosophila (78), non small cell lung cancer (79), and aggressive glioma (80) suggest an interplay among mitochondrial damage (78), TGFβ-induced actin remodeling (81), and loss of PRC2 activity (79) can all generate cell states that are permissive to YAP activation.…”

Regulatory T‐cell cytokines in patients with nonsegmental vitiligo

“…6 Immunosuppressive cytokines, including TGF-b and IL-10, contribute to the suppressor functions of Treg cells. 9 Moreover, TGF-b signaling acts as a tumor promoter in advanced epithelial tumors. 8 TGF-b is well-known to promote the epithelial-to-mesenchymal transition (EMT) and contribute to metastasis.…”

“…8 TGF-b is well-known to promote the epithelial-to-mesenchymal transition (EMT) and contribute to metastasis. 9 Moreover, TGF-b signaling acts as a tumor promoter in advanced epithelial tumors. [10][11][12] There is evidence for the contribution of Treg-cell deficiency in the development of autoimmune and inflammatory disorders, such as atopic dermatitis and inflammatory intestinal disease.…”