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Dormancy-inducing 3D engineered matrix uncovers mechanosensitive and drug-protective FHL2-p21 signaling axis

ABSTRACT: Solid cancers frequently relapse with distant metastasis, despite local and systemic treatment. Cellular dormancy has been identified as an important mechanism underlying drug resistance enabling late relapse. Therefore, relapse from invisible, minimal residual cancer of seemingly disease-free patients call for in vitro models of dormant cells suited for drug discovery. Here, we explore dormancy-inducing 3D engineered matrices, which generate mechanical confinement and induce growth arrest and survival against chemotherapy in cancer cells. We characterized the dormant phenotype of solitary cells by P-ERKlow:P-p38high dormancy signaling ratio, along with Ki67− expression. As underlying mechanism, we identified stiffness-dependent nuclear localization of the four-and-a-half LIM domain 2 (FHL2) protein, leading to p53-independent high p21Cip1/Waf1 nuclear expression, validated in murine and human tissue. Suggestive of a resistance-causing role, cells in the dormancy-inducing matrix became sensitive against chemotherapy upon FHL2 down-regulation. Thus, our biomaterial-based approach will enable systematic screens for previously unidentified compounds suited to eradicate potentially relapsing dormant cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182606 | GEO | 2024/08/21

REPOSITORIES: GEO

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Dormancy-inducing 3D engineered matrix uncovers mechanosensitive and drug-protective FHL2-p21 signaling axis

Project description:Dormancy-inducing 3D engineered matrix uncovers mechanosensitive and drug-protective FHL2-p21 signaling axis

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Osteoclasts Control Re-activation of Dormant Myeloma Cells by Remodeling the Endosteal Niche

Project description:Multiple myeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsic pathways. Disease relapse is thought to originate from dormant myeloma cells, localized in specialized niches, which resist therapy and re-populate the tumor. However, little is known about the niche, and how it exerts cell-extrinsic control over myeloma cell dormancy and re-activation. In this study we track individual myeloma cells by intravital imaging as they colonize the endosteal niche, enter a dormant state and subsequently become activated to form colonies. We demonstrate that dormancy is a reversible state which is switched ‘on’ by engagement with bone lining cells or osteoblasts, and switched ‘off’ by osteoclasts remodeling the endosteal niche. Dormant myeloma cells are resistant to chemotherapy targeting dividing cells. The demonstration that the endosteal niche is pivotal in controlling myeloma cell dormancy highlights the potential for targeting cell-extrinsic mechanisms to overcome cell-intrinsic drug resistance and prevent disease relapse.

2015-11-30 | GSE57695 | GEO

Differential expression between FHL2-/- and WT MEFs.

Project description:The LIM-only protein FHL2 acts as a transcriptional modulator that positively or negatively regulates multiple signaling pathways. We recently reported that FHL2 cooperates with CBP/p300 in the activation of ß-catenin/TCF target gene cyclin D1. In this paper, we demonstrate that FHL2 is associated with the cyclin D1 promoter at the TCF/CRE site, providing evidence that cyclin D1 is a direct target of FHL2. We show that deficiency of FHL2 greatly reduces the proliferative capacity of spontaneously immortalized mouse fibroblasts which is associated with decreased expression of cyclin D1 and p16INK4a, and hypophosphorylation of Rb. Reexpression of FHL2 in FHL2-null fibroblasts efficiently restores cyclin D1 levels and cell proliferative capacity, indicating that FHL2 is critical for cyclin D1 activation and cell growth. Moreover, ectopic cyclin D1 expression is sufficient to override growth inhibition of immortalized FHL2-null fibroblasts. Gene expression profiling revealed that FHL2 deficiency triggers a broad change of the cell cycle program that is associated with downregulation of several G1/S and G2/M cyclins, E2F transcription factors and DNA replication machinery, thus correlating with reduced cell proliferation. This change also involves downregulation of the negative cell cycle regulators, particularly INK4 inhibitors, which could counteract the decreased expression of cyclins, allowing cells to grow. Our study illustrates that FHL2 can act on different aspects of the cell cycle program to finely regulate cell proliferation. Keywords: mouse embryonic fibroblasts derived from FHL2-/- and WT mouse embryos (14.5 days)

2008-06-06 | GSE10902 | GEO

Early adipogenesis is repressed through the newly identified FHL2-NFAT5 signaling complex

Project description:The LIM-domain-only protein FHL2 is a modulator of signal transduction and has been shown to direct the differentiation of mesenchymal stem cells toward osteoblasts and myocytes phenotypes. We hypothesized that FHL2 may simultaneously interfere with the induction of the adipocyte lineage. Therefore, we investigated the role of FHL2 in adipocyte differentiation using pre-adipocytes isolated from mouse adipose tissue and the 3T3-L1 (pre)adipocyte cell line. Here we report that FHL2 is expressed in pre-adipocytes and for accurate adipocyte differentiation, this protein needs to be downregulated during the early stages of adipogenesis. More specifically, constitutive overexpression of FHL2 drastically inhibits adipocyte differentiation in 3T3-L1 cells, which was demonstrated by suppressed activation of the adipogenic gene expression program as shown by extensive RNAseq analyses, and diminished lipid accumulation. To identify the protein-protein interactions mediating this repressive activity of FHL2 on adipogenesis, we performed affinity-purification mass spectrometry (AP-MS). This analysis revealed the interaction of FHL2 with the Nuclear factor of activated T-cells 5 (NFAT5), an established inhibitor of adipocyte differentiation. NFAT5 knockdown rescued the inhibitory effect of FHL2 overexpression on 3T3-L1 differentiation, indicating that these proteins act cooperatively. In conclusion, we present a new regulatory function of FHL2 in early adipocyte differentiation and revealed that FHL2-mediated inhibition of pre-adipocyte differentiation is dependent on its interaction with NFAT5.

2023-11-13 | PXD033974 | Pride

Four-and-a-half LIM domain protein 2 (FHL2) deficiency protects mice from diet-induced obesity and high FHL2 expression correlates with obesity in man.

Project description:Four-and-a-Half-LIM-domain-protein 2 (FHL2) modulates multiple signal transduction pathways but has not been implicated in obesity or energy metabolism. In man, FHL2 expression increases with age and high FHL2 expression is associated with increased body weight in human and mice, leading us to hypothesize that FHL2 is a determinant of diet-induced obesity. Accordingly, loss of FHL2 protects mice from high-fat diet-induced weight gain. This is associated with enhanced energy expenditure in FHL2-/- mice. In an attempt to discover the origin of the increased energy expenditure in FHL2-/- mice, we performed transcriptome analysis (RNA-seq) on the heart, since FHL2 is highly expressed in this organ and gonadal white adipose tissue in WT and FHL2-/- mice.

2021-06-14 | GSE156027 | GEO

Gene expression analysis of FHL2-knockout mouse liver

2012-01-01 | GSE26904 | GEO

Gene expression analysis of FHL2-knockout mouse liver

Project description:FHL2 is known to be deregulated in liver cancer. In the present study, microarray gene expression profiling was performed to identify the genes regulated downstream of FHL2 In this dataset, we compared the RNA samples from livers of FHL2 knockout mice and those of wild-type (WT) mice. FHL2 knockout mice was initially generated by Chu et al. 2000. RNA from three mice per group (male, age: 10-11 weeks) were pooled and the two groups were subjected to analysis .

2012-01-01 | E-GEOD-26904 | biostudies-arrayexpress

Function of LIM-only protein FHL2 in vascular smooth muscle cells

Project description:The LIM-only protein FHL2 is expressed in SMCs and inhibits SMC-rich lesion formation. However, the underlying mechanism behind FHL2's action in SMCs has been only partially resolved. To further elucidate the role of FHL2 in SMCs we compared the transcriptome of cultured SMCs derived from wild-type (WT) and FHL2-knockout (KO) mice.

2014-10-07 | GSE56860 | GEO

Modeling androgen deprivation therapy-induced prostate cancer dormancy and its clinical implications

Project description:Purpose: Treatment-induced tumor dormancy is a state in cancer progression where residual disease is present but remains asymptomatic. Dormant cancer cells are treatment-resistant and responsible for cancer recurrence and metastasis. Prostate cancer (PCa) treated with androgen-deprivation therapy (ADT) often enters a dormant state. ADT-induced PCa dormancy remains poorly understood due to the challenge in acquiring clinical dormant PCa cells and the lack of representative models. We, therefore, aimed to develop clinically relevant models that can be used for studying ADT-induced PCa dormancy. Experimental design: Dormant PCa models were established by castrating mice bearing PCa patient-derived xenografts (PDXs) of hormonal naïve or sensitive PCa. Dormancy status and tumor relapse were monitored and evaluated. Paired pre- and post-castration (dormant) PDX tissues were subjected to morphological and transcriptome profiling analyses. Results: We established eleven ADT-induced dormant PCa models that closely mimicked the clinical courses of ADT-treated PCa. We identified two ADT-induced dormancy subtypes that differed in morphology, gene expression, and relapse rates. We discovered transcriptomic differences in pre-castration PDXs that predisposed the dormancy response to ADT. We further developed a dormancy subtype-based, predisposed gene signature that was significantly associated with ADT response in hormonal naïve PCa and clinical outcome in castration-resistant PCa treated with ADT or androgen-receptor pathway inhibitors.

2022-01-11 | GSE193500 | GEO

RNA-sequencing of D2A1 and D2.OR cell lines in both 2D and 3D cultures

Project description:Reactivation of dormant cancer cells can lead to cancer relapse, metastasis and patient death. Dormancy is a non-proliferative state and is linked to late relapse and death. No targeted therapy is currently available to eliminate dormant cells, highlighting the need for a deeper understanding and reliable models. Here, we thoroughly characterize the dormant D2.OR and proliferative D2A1 breast cancer cell line models in vivo and in vitro, and assess if there is overlap between a dormant and a senescent phenotype. We show that D2.OR but not D2A1 cells become dormant in the liver of an immunocompetent model. In vitro, we show that D2.OR cells are polyploid ER+/Her2+ cells, and in response to a 3D environment are growth arrested in G1, of which a subpopulation resides in a 4NG1 state. The dormancy state is reversible, and not associated with a senescence phenotype. This will aid future research on breast cancer dormancy.

2021-09-19 | GSE172882 | GEO

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