Elastin MIcrofibriL INterfacer1 (EMILIN‐1) is an alternative prosurvival VLA‐4 ligand in chronic lymphocytic leukemia

Tissino, Erika; Pivetta, Eliana; Capuano, Alessandra; Capasso, Guido; Bomben, Riccardo; Caldana, Chiara; Rossi, Francesca Maria; Pozzo, Federico; Benedetti, Dania; Boldorini, Renzo; Gaïdano, Gianluca; Rossi, Davide; Zamò, Alberto; Hartmann, Tanja Nicole; Doliana, Roberto; Colombatti, Alfonso; Gattei, Valter; Spessotto, Paola; Zucchetto, Antonella

doi:10.1002/hon.2947

Cited by 5 publications

(2 citation statements)

References 43 publications

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“…As previously discussed, VLA-4 is the main integrin responsible for the interaction between CLL cells and the cellular as well as a-cellular components of the microenvironment, such as BM MSCs, FDCs, ECs, and fibronectin. VLA-4 is capable of reducing spontaneous apoptosis in vitro in CLL cells cultured in the presence of its recombinant ligands, such as VCAM-1, fibronectin, and the globular C1q (gC1q) domain of elastin microfibrilinterfacer-1 (EMILIN-1) [178,179]. Moreover, engagement of VLA-4 by recombinant fibronectin protects CLL cells from fludarabine-induced apoptosis, in particular cells expressing high levels of CD49d [155].…”

Section: Cell Adhesion-mediated Drug Resistance In Cllmentioning

confidence: 99%

The Role of the Microenvironment and Cell Adhesion Molecules in Chronic Lymphocytic Leukemia

Cerreto,

Foà,

Natoni

2023

Cancers

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Chronic lymphocytic leukemia (CLL) is a B-cell malignancy whose progression largely depends on the lymph node and bone marrow microenvironment. Indeed, CLL cells actively proliferate in specific regions of these anatomical compartments, known as proliferation centers, while being quiescent in the blood stream. Hence, CLL cell adhesion and migration into these protective niches are critical for CLL pathophysiology. CLL cells are lodged in their microenvironment through a series of molecular interactions that are mediated by cellular adhesion molecules and their counter receptors. The importance of these adhesion molecules in the clinic is demonstrated by the correlation between the expression levels of some of them, in particular CD49d, and the prognostic likelihood. Furthermore, novel therapeutic agents, such as ibrutinib, impair the functions of these adhesion molecules, leading to an egress of CLL cells from the lymph nodes and bone marrow into the circulation together with an inhibition of homing into these survival niches, thereby preventing disease progression. Several adhesion molecules have been shown to participate in CLL adhesion and migration. Their importance also stems from the observation that they are involved in promoting, directly or indirectly, survival signals that sustain CLL proliferation and limit the efficacy of standard and novel chemotherapeutic drugs, a process known as cell adhesion-mediated drug resistance. In this respect, many studies have elucidated the molecular mechanisms underlying cell adhesion-mediated drug resistance, which have highlighted different signaling pathways that may represent potential therapeutic targets. Here, we review the role of the microenvironment and the adhesion molecules that have been shown to be important in CLL and their impact on transendothelial migration and cell-mediated drug resistance. We also discuss how novel therapeutic compounds modulate the function of this important class of molecules.

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Section: Cell Adhesion-mediated Drug Resistance In Cllmentioning

confidence: 99%

The Role of the Microenvironment and Cell Adhesion Molecules in Chronic Lymphocytic Leukemia

Cerreto,

Foà,

Natoni

2023

Cancers

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“…The integrin consists of an alpha4 (CD49d) and a beta1 (CD29) subunit [ 3 ]. The major VLA-4 ligands are VCAM-1 and fibronectin [ 35 , 36 ]; however, ligands such as EMILIN-1 or osteopontin are also bound by VLA-4 [ 37 , 38 , 39 ]. In solid tumors, VCAM-1-VLA-4 interactions for example enhance metastasis of melanoma and breast cancer and reduce susceptibility to chemotherapy in ovarian cancer [ 40 , 41 , 42 ].…”

Section: Vla-4 Signaling—the Inside-out Cascadementioning

confidence: 99%

Integrin Signaling Shaping BTK-Inhibitor Resistance

Polcik

Prosseda

Pozzo

et al. 2022

Cells

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Integrins are adhesion molecules that function as anchors in retaining tumor cells in supportive tissues and facilitating metastasis. Beta1 integrins are known to contribute to cell adhesion-mediated drug resistance in cancer. Very late antigen-4 (VLA-4), a CD49d/CD29 heterodimer, is a beta1 integrin implicated in therapy resistance in both solid tumors and haematological malignancies such as chronic lymphocytic leukemia (CLL). A complex inside-out signaling mechanism activates VLA-4, which might include several therapeutic targets for CLL. Treatment regimens for this disease have recently shifted towards novel agents targeting BCR signaling. Bruton’s tyrosine kinase (BTK) is a component of B cell receptor signaling and BTK inhibitors such as ibrutinib are highly successful; however, their limitations include indefinite drug administration, the development of therapy resistance, and toxicities. VLA-4 might be activated independently of BTK, resulting in an ongoing interaction of CD49d-expressing leukemic cells with their surrounding tissue, which may reduce the success of therapy with BTK inhibitors and increases the need for alternative therapies. In this context, we discuss the inside-out signaling cascade culminating in VLA-4 activation, consider the advantages and disadvantages of BTK inhibitors in CLL and elucidate the mechanisms behind cell adhesion-mediated drug resistance.

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The survival grip–how cell adhesion promotes tumor maintenance within the microenvironment

Gardano,

Ferreira,

Le Roy

et al. 2024

FEBS Letters

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Cell adhesion is warranted by proteins that are crucial for the maintenance of tissue integrity and homeostasis. Most of these proteins behave as receptors to link adhesion to the control of cell survival and their expression or regulation are often altered in cancers. B‐cell malignancies do not evade this principle as they are sustained in relapsed niches by interacting with the microenvironment that includes cells and their secreted factors. Focusing on chronic lymphocytic leukemia and mantle cell lymphoma, this Review delves with the molecules involved in the dialog between the adhesion platforms and signaling pathways known to regulate both cell adhesion and survival. Current therapeutic strategies disrupt adhesive structures and compromise the microenvironment support to tumor cells, rendering them sensitive to immune recognition. The development of organ‐on‐chip and 3D culture systems, such as spheroids, have revealed the importance of mechanical cues in regulating signaling pathways to organize cell adhesion and survival. All these elements contribute to the elaboration of the crosstalk of lymphoma cells with the microenvironment and the education processes that allow the establishment of the supportive niche.

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Elastin MIcrofibriL INterfacer1 (EMILIN‐1) is an alternative prosurvival VLA‐4 ligand in chronic lymphocytic leukemia

Cited by 5 publications

References 43 publications

The Role of the Microenvironment and Cell Adhesion Molecules in Chronic Lymphocytic Leukemia

The Role of the Microenvironment and Cell Adhesion Molecules in Chronic Lymphocytic Leukemia

Integrin Signaling Shaping BTK-Inhibitor Resistance

The survival grip–how cell adhesion promotes tumor maintenance within the microenvironment

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