WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion

Rodríguez-Hernández, Irene; Maiques, Óscar; Kohlhammer, Leonie; Cantelli, Gaia; Perdrix-Rosell, Anna; Monger, Joanne; Fanshawe, Bruce; Bridgeman, Victoria L.; Karagiannis, Sophia N.; Penín, R.M.; Marcolval, Joaquim; Martí, Rosa M.; Matías‐Guiu, Xavier; Fruhwirth, Gilbert O.; Orgaz, José L.; Malanchi, Ilaria; Sanz-Moreno, Victoria

doi:10.1038/s41467-020-18951-2

Cited by 75 publications

(105 citation statements)

References 70 publications

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“…These findings are in agreement with previous observations of rounded melanoma cells moving through Matrigel and in tumor xenografts in mice (Pinner and Sahai, 2008;Sahai and Marshall, 2003;Sanz-Moreno et al, 2011. They are also supported by histological analysis of melanoma in the tumor periphery, where a rounded morphology was found to be associated with cell invasion (Georgouli et al, 2019;Rodriguez-Hernandez et al, 2020).…”

Section: Resultssupporting

confidence: 92%

Proteolysis-free cell migration through crowded environments via mechanical worrying

Welf

Driscoll

Sapoznik

et al. 2020

Preprint

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Migratory cells employ numerous strategies to navigate the very diverse 3D microenvironments found in vivo. These strategies are subdivided into those that create space by pericellular proteolysis of extracellular matrix (ECM) proteins and those that navigate existing spaces. We find that cells can employ an alternative mechanism by digging tunnels through 3D collagen networks without extracellular proteolysis. This is accomplished by persistent polarization of large dynamic membrane blebs at the closed end of the tunnel that repeatedly agitate the collagen, a process we termed mechanical worrying. We find that this agitation promotes breakage and internalization of collagen at the cell front along with extracellular fluid in a macropinocytosis-driven manner. Membrane blebs are short-lived relative to the timescale of migration, and thus their polarization is critical for persistent ablation of the ECM. We find that sustained interactions between the collagen at the cell front and small but persistent cortical adhesions induce PI-3 Kinase (PI3K) signaling that drives polarized bleb enlargement via the Rac1 – Arp2/3 pathway. This defines a mechanism for the reinforcement of bleb expansion against load, which enables precise ablation of mechanically unrestrained environments, such as those encountered in very compliant tissue.

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Section: Resultssupporting

confidence: 92%

Proteolysis-free cell migration through crowded environments via mechanical worrying

Welf

Driscoll

Sapoznik

et al. 2020

Preprint

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“…Among these, Daam1 might have an important role in GC since high DAAM1 expression correlates with lower survival, using terciles ( Supplementary Figure 10 ). Of note, Daam1 has been associated with cancer progression in other tissues ( Zhu et al, 2012 ; Wu et al, 2019 ; Rodriguez-Hernandez et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

A Non-canonical Wnt Signature Correlates With Lower Survival in Gastric Cancer

Astudillo

2021

Front. Cell Dev. Biol.

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Genetic evidence suggests a role for the Wnt/β-catenin pathway in gastric cancer. However, Wnt5a, regarded as a prototypical non-canonical Wnt ligand, has also been extensively associated with this disease. Therefore, the roles of the Wnt signaling pathway in gastric cancer initiation and progression, and particularly the precise mechanisms by which the non-canonical Wnt pathway might promote the development and progression of gastric cancer, are not entirely well understood. This article analyzes publicly available gene and protein expression data and reveals the existence of a WNT5A/FZD2/FZD7/ROR2 signature, which correlates with tumor-infiltrating and mesenchymal cell marker expression. High expression of FZD7 and ROR2 correlates with a shared gene and protein expression profile, which in turn correlates with poor prognosis. In summary, the findings presented in this article provide an updated view of the relative contributions of the Wnt/β-catenin and non-canonical Wnt pathways in gastric cancer.

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“…In this work, we provide evidence that ROCK-Myosin II activation in cancer cells with basal characteristics represents an important modulator for the initiation of their characteristic TME in vivo. When cancer cells have high ROCK-Myosin II activation, this is generally required for their intrinsic tumourigenicity (Rodriguez-Hernandez et al 2020;Kümper et al 2016), but we identify a murine cell line which represented an exception. Indeed, the aggressive murine 4T1 breast cancer maintained its highly proliferative activity in various in vitro conditions upon ROCK-Myosin II inhibition but showed a perturbed fibroblast activation ability.…”

Section: Discussionmentioning

confidence: 96%

Early functional mismatch between breast cancer cells and their tumour microenvironment suppresses long term growth

Maiques

Chakravarty

et al. 2021

Preprint

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Cancer cells thrive embedded in a fine-tuned cellular and extracellular environment or tumour microenvironment (TME). There is the general understanding of a co-evolution between cancer cells and their surrounding TME, suggesting a functional connection between cancer cells characteristics and the perturbations induced in their surrounding tissue. However, this functional connection has never been formally proven with a dedicated experimental setting. Here we provide experimental evidence that when aggressive cancer cells are forced to initially establish an alternative TME, this will evolve to impair long term in vivo cancer growth. Using a combination of in vivo transcriptomics, protein arrays and in vitro co-cultures, we found that this alternative TME culminates in the infiltration of macrophages with STAT1high activity. Despite lacking canonical M1 markers, these macrophages show strong anti-tumoural functions which reduce long-term tumour growth. Importantly, gene signatures of stromal cell, the major cellular component in the alternative TME as well as the alternative activated macrophages show striking prognostic power, correlating with less aggressive human breast cancers.

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WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion

Cited by 75 publications

References 70 publications

Proteolysis-free cell migration through crowded environments via mechanical worrying

Proteolysis-free cell migration through crowded environments via mechanical worrying

A Non-canonical Wnt Signature Correlates With Lower Survival in Gastric Cancer

Early functional mismatch between breast cancer cells and their tumour microenvironment suppresses long term growth

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