Reduced Lamin A/C Does Not Facilitate Cancer Cell Transendothelial Migration but Compromises Lung Metastasis

Roncato, Francesco; Regev, Ofer; Feigelson, Sara W.; Yadav, Sandeep Kumar; Kaczmarczyk, Lukasz; Levi, Nehora; Drago-García, Diana; Ovadia, Samuel; Kizner, Marina; Addadi, Yoseph; Sabino, João C.; Ovadya, Yossi; Almeida, Sérgio Fernandes de; Feldmesser, Ester; Gerlitz, Gabi; Alon, Ronen

doi:10.3390/cancers13102383

Cited by 19 publications

(17 citation statements)

References 65 publications

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“…Immediately after the sacrifice, mice were transcardially perfused with PBS and the lungs were inflated via the trachea with low-gelling agarose (Cat. A9045, Sigma-Aldrich), fixed with paraformaldehyde (4% in PBS) for 2 h, dehydrated, and cleared using ethyl cinnamate as described ( 40 , 41 ). Cleared lung lobes were imaged in an Ultramicroscope II (LaVision BioTec) operated by the ImspectorPro software (LaVision BioTec, Bielefeld, Germany) as described ( 41 ).…”

Section: Methodsmentioning

confidence: 99%

ICAM-1 on Breast Cancer Cells Suppresses Lung Metastasis but Is Dispensable for Tumor Growth and Killing by Cytotoxic T Cells

et al. 2022

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Breast tumors and their derived circulating cancer cells express the leukocyte β2 integrin ligand Intercellular adhesion molecule 1 (ICAM-1). We found that elevated ICAM-1 expression in breast cancer cells results in a favorable outcome and prolonged survival of breast cancer patients. We therefore assessed the direct in vivo contribution of ICAM-1 expressed by breast cancer cells to breast tumorigenesis and lung metastasis in syngeneic immunocompetent mice hosts using spontaneous and experimental models of the lung metastasis of the C57BL/6-derived E0771 cell line, a luminal B breast cancer subtype. Notably, the presence of ICAM-1 on E0771 did not alter tumor growth or the leukocyte composition in the tumor microenvironment. Interestingly, the elimination of Tregs led to the rapid killing of primary tumor cells independently of tumor ICAM-1 expression. The in vivo elimination of a primary E0771 tumor expressing the ovalbumin (OVA) model neoantigen by the OVA-specific OVA-tcr-I mice (OT-I) transgenic cytotoxic T lymphocytes (CTLs) also took place normally in the absence of ICAM-1 expression by E0771 breast cancer target cells. The whole lung imaging of these cells by light sheet microscopy (LSM) revealed that both Wild type (WT)- and ICAM-1-deficient E0771 cells were equally disseminated from resected tumors and accumulated inside the lung vasculature at similar magnitudes. ICAM-1-deficient breast cancer cells developed, however, much larger metastatic lesions than their control counterparts. Strikingly, the vast majority of these cells gave rise to intravascular tumor colonies both in spontaneous and experimental metastasis models. In the latter model, ICAM-1 expressing E0771- but not their ICAM-1-deficient counterparts were highly susceptible to elimination by neutrophils adoptively transferred from E0771 tumor-bearing donor mice. Ex vivo, neutrophils derived from tumor-bearing mice also killed cultured E0771 cells via ICAM-1-dependent interactions. Collectively, our results are a first indication that ICAM-1 expressed by metastatic breast cancer cells that expand inside the lung vasculature is involved in innate rather than in adaptive cancer cell killing. This is also a first indication that the breast tumor expression of ICAM-1 is not required for CTL-mediated killing but can function as a suppressor of intravascular breast cancer metastasis to lungs.

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Section: Methodsmentioning

confidence: 99%

ICAM-1 on Breast Cancer Cells Suppresses Lung Metastasis but Is Dispensable for Tumor Growth and Killing by Cytotoxic T Cells

et al. 2022

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“…The dynamic interaction of the nucleus with the actomyosin cytoskeleton is required to ensure proper nuclear deformation to successfully squeeze the cell through small but not through large constrictions [ 52 , 53 ]. We have recently shown that nucleus deformation is the rate-limiting step for Β16F10 to pass through constrictions smaller than the nucleus [ 39 ]. Since ZMP-treated Β16F10 cells failed to cross large pores, these results suggest that interference with MT disassembly blocks the chemotaxis and haptotaxis of these cells at a distinct step, possibly prior to actomyosin-driven nuclear deformation.…”

Section: Resultsmentioning

confidence: 99%

“…Cancer cell TEM in vitro involves sequential steps ( Figure 2a ): spreading over the EC surface, protrusion through paracellular EC junctions, generation of a stable subendothelial pseudopodia that displaces the EC attachments to the endothelial-deposited ECM (basement membrane) and nucleus squeezing below the endothelial monolayer [ 39 ] ( Figure 2b and Videos 3 and 4). As expected, interference with actin turnover using Jasp blocked tumor TEM by abolishing the ability of Β16F10 cells to initially spread over the EC monolayer ( Figure 2c ).…”

Section: Resultsmentioning

confidence: 99%

“…In the present study, we have compared the contribution of MT dynamics to directional cancer cell and immune cell migration through confined spaces as well as through endothelial barriers, a motility known as transendothelial migration (TEM), that is a critical checkpoint in cancer metastasis [ 37 , 38 ]. We chose the prototypic metastatic Β16F10 melanoma as a model for cancer cell TEM and metastasis due to its ability to cross murine endothelial monolayers in vitro and extravasate the pulmonary capillary bed in vivo [ 39 ]. We also chose effector T cells as a prototype of highly migratory leukocytes that cross endothelial monolayers in response to chemotactic cues [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

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Microtubule destabilization is a critical checkpoint of chemotaxis and transendothelial migration in melanoma cells but not in T cells

Roncato

Regev

Yadav

et al. 2021

Cell Adhesion & Migration

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Microtubules (MTs) control cell shape and intracellular cargo transport. The role of MT turnover in the migration of slow-moving cells through endothelial barriers remains unclear. To irreversibly interfere with MT disassembly, we have used the MT-stabilizing agent zampanolide (ZMP) in Β16F10 melanoma as amodel of slow-moving cells. ZMP-treated B16 cells failed to follow chemotactic gradients across rigid confinements and could not generate stable sub-endothelial pseudopodia under endothelial monolayers. In vivo, ZMP-treated Β16 cells failed to extravasate though lung capillaries. In contrast to melanoma cells, the chemotaxis and transendothelial migration of ZMP-treated Tcells were largely conserved. This is afirst demonstration that MT disassembly is akey checkpoint in the directional migration of cancer cells but not of lymphocytes.

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“…Notably, PME-1 physically associates with the nuclear lamina (NL) ([37] and Figure S4A,B) and regulates phosphorylation of lamins, key structural components of the NL, but also other related proteins such as LAP2A/B that connect the NL to chromatin (Figure S4C). It has previously been shown that NL directly influences chromatin architecture [38, 39], and that de-regulation of the NL can lead to DNA damage and cell death, limiting both cancer cell growth in soft agar and metastasis [38, 40, 41]. Therefore, we next assessed whether PME-1 inhibition could alter nuclear structure and stability.…”

Section: Resultsmentioning

confidence: 99%

PME-1 suppresses anoikis and is associated with therapy relapse of PTEN-deficient prostate cancers

Rupp

Aakula

Isomursu

et al. 2019

Preprint

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33Identification of novel mechanisms of apoptosis resistance of prostate cancer (PCa) 34 cells has translational importance. Here, we discover that inhibition of tumor 35 suppressor phosphatase PP2A by PME-1 inhibits anoikis (apoptosis in anchorage-36 independent conditions) in PTEN-deficient PCa cells. PME-1 physically associated 37 with the nuclear lamina and regulated its deformability in PCa cells. In addition, PME-38 1 deficient cells, with highly deformable nuclear lamina, were particularly vulnerable to 39 anoikis following cell detachment. As a molecular explanation for increased nuclear 40 lamina deformability, PME-1 depletion induced dephosphorylation of nuclear lamina 41 constituents, Lamin-A/C, Lamin-B1, Lamin-B2, LAP2A, LAP2B, and NUP98. PME-1 42 inhibition increased apoptosis also in an in ovo tumor model, and attenuated cell 43 survival in zebrafish circulation. Clinically, PCa patients with inhibition of both PP2A 44 and PTEN tumor suppressor phosphatases (PME-1 high /PTEN loss ), have less than 50% 455-year secondary-therapy free patient survival, which is significantly shorter than 46 survival of patients with only PTEN-deficient tumors. 47In summary, we discover that PME-1 overexpression supports anoikis 48 resistance in PTEN-deficient PCa cells. Further, increased nuclear lamina 49 deformability was identified as plausible target mechanism sensitizing PME-1-50 depleted cells to anoikis. Clinically, the results identify PME-1 as a novel candidate 51 biomarker for particularly aggressive PTEN-deficient PCa. 52 53 55 56 3 57 Clinical relevance 58 59 While organ-confined PCa is mostly manageable, the local and distant metastatic 60 progression of PCa remains a clinical challenge. Resistance to anoikis is critical for 61 PCa progression towards aggressive CRPC. Our data show that PME-1 expression in 62 human PCa cells protects the cells from apoptosis induction in anchorage-63 independent conditions both in vitro and in vivo. Clinically, our results identify PME-1 64 as a novel putative biomarker for extremely poor prognosis in PTEN-deficient PCa. 65 Taken together, our results demonstrate novel post-translational regulation of key 66 cancer progression mechanisms, with clear translational implications. 67 68 (4), and prostate-specific PTEN deletion in a mouse model leads to metastatic PCa 87 (5). Importantly, both PTEN deletion, and hyperactivity of PTEN downstream target 88 AKT increases anoikis resistance (6-8). On the other hand, recent studies in other 89cancer types indicate for a very delicate balance between nuclear lamina stiffness and 90 anchorage-independence, anoikis resistance, and cell migration. Whereas cell 91 migration in three dimensional contexts requires a sufficiently deformable nuclear 92 lamina to allow passage through physical restrictions (9-11), too deformable nuclei may limit cancer cell survival especially in anchorage-independent conditions (9, 12-94 15). Of nuclear lamina proteins, particularly inhibition of both Lamin-A/C and Lamin-95

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Reduced Lamin A/C Does Not Facilitate Cancer Cell Transendothelial Migration but Compromises Lung Metastasis

Cited by 19 publications

References 65 publications

ICAM-1 on Breast Cancer Cells Suppresses Lung Metastasis but Is Dispensable for Tumor Growth and Killing by Cytotoxic T Cells

ICAM-1 on Breast Cancer Cells Suppresses Lung Metastasis but Is Dispensable for Tumor Growth and Killing by Cytotoxic T Cells

Microtubule destabilization is a critical checkpoint of chemotaxis and transendothelial migration in melanoma cells but not in T cells

PME-1 suppresses anoikis and is associated with therapy relapse of PTEN-deficient prostate cancers

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