The topology of vitronectin: A complementary feature for neuroblastoma risk classification based on computer‐aided detection

Abstract

Tumors are complex networks of constantly interacting elements: tumor cells, stromal cells, immune and stem cells, blood/lympathic vessels, nerve fibers and extracellular matrix components. These elements can influence their microenvironment through mechanical and physical signals to promote tumor cell growth. To get a better understanding of tumor biology, cooperation between multidisciplinary fields is needed. Diverse mathematic computations and algorithms have been designed to find prognostic targets and enhance diagnostic assessment. In this work, we use computational digital tools to study the topology of vitronectin, a glycoprotein of the extracellular matrix. Vitronectin is linked to angiogenesis and migration, two processes closely related to tumor cell spread. Here, we investigate whether the distribution of this molecule in the tumor stroma may confer mechanical properties affecting neuroblastoma aggressiveness. Combining image analysis and graph theory, we analyze different topological features that capture the organizational cues of vitronectin in histopathological images taken from human samples. We find that the Euler number and the branching of territorial vitronectin, two topological features, could allow for a more precise pretreatment risk stratification to guide treatment strategies in neuroblastoma patients. A large amount of recently synthesized VN would create migration tracks, pinpointed by both topological features, for malignant neuroblasts, so that dramatic change in the extracellular matrix would increase tumor aggressiveness and worsen patient outcomes.

Impact of extracellular matrix properties on neuroblastoma genomic heterogeneity

“…Both niches, which initially lacked VN, showed a large amount of VN secreted by neuroblats [22]. Our results show new evidence for the probably role of VN in biotensegrity mechanotransduction by mediating the cellular response to ECM stiffness [22,56]. The adaptation process was faster in VN-KO tumor cells but less manageable than in hydrogels.…”

“…In previous studies, we demonstrated that elevated VN secretion by tumor cells was founded in rigid ECMs, and was related to poor patient outcomes and to growth of orthotopically inoculated NB cell lines [22]. Moreover, we observed that the high amount of VN is secreted forming tracks and we postulated that VN participates in stiffness, mediating biotensegrity and promoting tumor migration in HR-NB [22,56]. We also reported that SK-N-BE(2) cells grown in stiff 3D hydrogels show more e cient adaptation, increased cell proliferation, high expression of the Bcl2 antiapoptosis marker, and high mRNA processing rate (24).…”

“…HG° and HG^= neuroblasts cultured in hydrogels only and coculture with Schwann cells, respectively, followed by the percentage of AlgMA (%) and the weeks of culture (w). Tumor samples from the experimental RAG1−/− VN−/− mice (VN-KO) and control in the sample (25)). When the percentage is less than 30% the background color of the aberration is lighter.…”

“…NB stiff ECM is also rich in collagen I bers and bronectin but in less amount and with a more physiological-like topology than collagen III and VN [18,23] Moreover, VN is a glycoprotein containing multiple cell receptor binding sites including integrins, uPAR and PAI-1 [24], and which can therefore form transitory ECM elements-cell junctions. It seems to anchorage to ECM bers and proteoglycans, as well as disrupted cell adhesion, promoting spreading and metastasis in NB [22,25]. Some studies have shown an important role for VN in initiation and progression of hepatic [26], breast [27] and lung [28] cancers, and its particular involvement in migration in ovarian cancer [29,30].…”

Impact of extracellular matrix stiffness on genomic heterogeneity in MYCN-amplified neuroblastoma cell line

“…NB stiff ECM is rich in cross-linked collagen III bers, poor in glycosaminoglycans, supporting sinusoidal vascular structures (blood and lymphatic) and with a high quantity of territorial vitronectin (VN, located in the cytoplasmic compartment and in a thin layer around the tumor cells) [19][20][21][22]. NB stiff ECM is also rich in collagen I bers and bronectin but in lesser amounts and with a more physiologicallike topology than collagen III and VN [18,23] Moreover, VN is a glycoprotein containing multiple cell receptor binding sites including integrins, uPAR and PAI-1 [24], and which can therefore form transitory ECM element-cell junctions. It seems to anchor to ECM bers and proteoglycans, and also disrupt cell adhesion, promoting spread and metastasis in NB [22,25].…”