Tumor ECM: the highway to cell

Figure 1: Tumor-cell macrophage pairing and stimulated motility Courtesy of Landes Bioscience, reproduced from IntraVital 2012;1(1): 77-85.

Tumor MTLn3 + BMM macrophages

Ved Sharma, from the Albert Einstein College of Medicine, has recently published under the guidance of Robert Eddy a paper

in the new journal IntraVital, presenting their analysis of an in vitro model for macrophage-tumor cell pairing and streaming, a phenomenon

recently discovered in vivo, involved in tumor cell invasion and metastasis. The study, conducted on micropatterned lines, demonstrates the relevance of this model for

cell-based screening in cancer genetics and drug discovery.

Collagen fibers of the tumor extracellular matrix have been identified as deeply involved in the organization and facilitation of streaming migration for breast tumor cells in vivo. This phenomenon is

linked to the progression of cancers, and more specifically with the metastatic spread.

Ved Sharma et al have managed to reproduce in vivo motility behaviors in an in vitro model of fibrillar tumor ECM, based on the use of CYTOO micropatterned line substrates, designed to mimic the linear fibers of the tumor microenvironment. Combining micropatterning and different imaging approaches -including intravital imaging- the authors conducted a side by side comparison of mammary tumor cell motility and the interactions occurring between cancers and stromal cells both in 1D, 2D and in vivo environments.

Similar morphologies, behaviors and motility rates were observed in vivo and on micropatterned 1D lines. In particular, tumor cell velocity on 1D substrates was in agreement with the high velocity values of tumor cells on ECM fibers observed in vivo. In contrast, on classical 2D substrates, motility rates were ten fold lower than what can be observed in vivo.

On micropatterned lines, the authors could also reproduce the assembly of alternating tumor cells and macrophages identified as streams in vivo, the ability of macrophages to enhance protrusion velocity

and average velocity of tumor cells and showed that this effect was dependent on an intact paracrine loop without any additional need of co-factors.

“It was a surprise that tumor cell and macrophage streaming behavior we observe in the highly complex tumor microenvironment was self-organizing and required no other extracellular cues on 1D adhesive substrates”Robert Eddy, Albert Einstein College of Medicine, NY, USA

Sharma concluded the IntraVital paper with enthusiatic words: ”our 1D micropatterned substrate model more closely approximates the fibrillar

nature of the in vivo tumor microenvironment and offers a simple and more appropriate substrate for detailed analyses of cell protrusion, cell-cell pairing and

migration than conventional 2D substrates. The data presented here validates the use of micropatterned 1D adhesive substrates to study the fibrillar ECM found within the tumor

microenvironment. The composition and geometry of the 1D micropatterned substrate can be easily customized in order to study the role of the ECM during high velocity tumor cell migration, cell-cell

pairing and streaming.“

According to Manuel Théry (Phd, CEA): “this paper is the demonstration of the pertinence of assays that can be conducted on CYTOOchipsTM Motility, and of their physiological relevance. Sharma et al demonstrated here that 1D micropatterning can successfully reproduce in vivo conditions to study the fibrillar ECM within the tumor microenvironment. Thanks to this scientific demonstration, micropatterns can now be seriously considered as a complementary tool to intravital imaging to study fibrillar ECM-dependent cell pairing, migration and relay

chemotaxis. This may open new perspectives for future works in oncology, genetics, and drug screening.”

Figure 2: Mimicking the fibrillar ECM of the tumor microenvironment on 1D micropatterned lines Images show in vivo streaming migration and 1D cell migration, both presenting tumor cells alternating with macrophages.

Courtesy of Landes Bioscience, reproduced from IntraVital 2012;1(1):77-85.

Further reading: Sharma V, Beaty B, Patsialou A, et al. Reconstitution of in vivo macrophage-tumor cell pairing and streaming motility on one-dimensional micro-patterned substrates. IntraVital. 2012;1(1):77-85.

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