Constitutive Activation of STAT3 in Myeloma Cells Cultured in a Three-Dimensional, Reconstructed Bone Marrow Model

Huang, Yung-Hsing; Molavi, Ommoleila; Alshareef, Abdulraheem; Haque, Moinul; Wang, Qian; Chu, Michael P.; Venner, Christopher P.; Sandhu, Irwindeep; Peters, Anthea; Lavasanifar, Afsaneh; Lai, Raymond

doi:10.20944/preprints201803.0151.v1

Cited by 3 publications

(6 citation statements)

References 33 publications

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“…Based on our data, along with the public cohort that shows that PBK expression is significantly associated with poor prognosis in MM patients with t(4;14), it is possible that the involvement of PBK in tumor growth is more obvious in MM cells with t(4;14). The t(4;14) translocation is known to cause the concomitant overexpression of 2 genes, fibroblast growth factor receptor 3 ( FGFR3 ) and multiple myeloma SET domain ( MMSET ), both of which exert growth advantage effects (Keats and others 2003 , 2005 ; Santra and others 2003 ; Huang and others 2018 ). As such, PBK may cooperate with FGFR3 and/or MMSET to promote tumor growth of MM cells.…”

Section: Discussionmentioning

confidence: 99%

“…Stat3 plays a pivotal role in the survival of MM cells (Takeda and others 1997 ; Alas and Bonavida 2003 ; Bharti and others 2004 ; Brocke-Heidrich and others 2004 ; Jung and others 2017 ; Huang and others 2018 ). Our data showed that knockout of PBK expression decreased, and rescue of its expression in PBK −/− cells increased the phosphorylation level of Stat3.…”

Section: Discussionmentioning

confidence: 99%

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Novel Interleukin-6 Inducible Gene PDZ-Binding Kinase Promotes Tumor Growth of Multiple Myeloma Cells

Ota

Hanamura

Karnan

et al. 2020

Journal of Interferon & Cytokine Research

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Multiple myeloma (MM) remains an intractable hematological malignancy, despite recent advances in anti-MM drugs. Here, we show that role of PDZ binding kinase (PBK) in MM tumor growth. We identified that interleukin-6 (IL-6) readily increases PBK expression. Kaplan–Meier analysis showed that the MM patients with higher expression of PBK have a significant shorter survival time compared with those with moderate/lower expression of PBK. Knockout of PBK dramatically suppressed in vivo tumor growth in MM cells, while genome editing of PBK changing from asparagine to serine substitution (rs3779620) slightly suppresses the tumor formation. Mechanistically, loss of PBK increased the number of apoptotic cells with concomitant decrease in the phosphorylation level of Stat3 as well as caspase activities. A novel PBK inhibitor OTS514 significantly decreased KMS-11-derived tumor growth. These findings highlight the novel oncogenic role of PBK in tumor growth of myeloma, and it might be a novel therapeutic target for the treatment of patients with MM.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Novel Interleukin-6 Inducible Gene PDZ-Binding Kinase Promotes Tumor Growth of Multiple Myeloma Cells

Ota

Hanamura

Karnan

et al. 2020

Journal of Interferon & Cytokine Research

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“…Some years later, Parikh et al [ 53 ] and then Huang et al [ 54 ] used an optimized protocol of Kirshner’s rBM model, in order to study the activation of the STAT3 pathway in 3D versus conventional 2D cultures. Specifically, the 3D culture was formed in a well with histogel that could be easily fixed, thus allowing for further histologic processing and immunocytochemical studies.…”

Section: 3d Ex Vivo Platforms Using Gel Scaffoldsmentioning

confidence: 99%

“…Specifically, the 3D culture was formed in a well with histogel that could be easily fixed, thus allowing for further histologic processing and immunocytochemical studies. Huang et al [ 54 ] showed that the STAT3 pathway was activated when cells were cultured in 3D, while it remained inactive in conventional 2D cultures. Inhibition of the STAT3 pathway using the pharmacological agent Stattic significantly decreased the viability of MM cells and increased their susceptibility to bortezomib.…”

Section: 3d Ex Vivo Platforms Using Gel Scaffoldsmentioning

confidence: 99%

“…Inhibition of the STAT3 pathway using the pharmacological agent Stattic significantly decreased the viability of MM cells and increased their susceptibility to bortezomib. These results were important as MM cells within the BM are also STAT3 active, thus implying that 3D models are superimposing 2D approaches and can better mimic the in vivo state [ 54 ].…”

Section: 3d Ex Vivo Platforms Using Gel Scaffoldsmentioning

confidence: 99%

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Ex Vivo Models Simulating the Bone Marrow Environment and Predicting Response to Therapy in Multiple Myeloma

Papadimitriou

Kostopoulos

Tsopanidou

et al. 2020

Cancers

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Multiple myeloma (MM) remains incurable despite the abundance of novel drugs. As it has been previously shown, preclinical 2D models fail to predict disease progression due to their inability to simulate the microenvironment of the bone marrow. In this review, we focus on 3D models and present all currently available ex vivo MM models that fulfil certain criteria, such as development of complex 3D environments using patients’ cells and ability to test different drugs in order to assess personalized MM treatment efficacy of various regimens and combinations. We selected models representing the top-notch ex vivo platforms and evaluated them in terms of cost, time-span, and feasibility of the method. Finally, we propose where such a model can be more informative in a patient’s treatment timeline. Overall, advanced 3D preclinical models are very promising as they may eventually offer the opportunity to precisely select the optimal personalized treatment for each MM patient.

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Oligo (p-Phenylene Vinylene)/Polyisocyanopeptide Biomimetic Composite Hydrogel-Based Three-Dimensional Cell Culture System for Anticancer and Antibacterial Therapeutics

Guo

Xing

Yuan

et al. 2019

ACS Appl. Bio Mater.

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Cells are normally cultured in 2D environment, which is usually inconsistent with the real microenvironment in vivo, and it is rarely reported that an effective cancer cell killing process occurs in a 3D network environment. Herein, a kind of new biomimetic composite hydrogel which can achieve 3D cell culture has been prepared and constructed by assembly of polyisocyanopeptide (PIC) with cationic oligo (p-phenylene vinylene) (OPV). The polymer chains of PIC can be bound and frizzled to form a 3D network when the temperature rises above the gelation temperature, followed by encapsulating the cells into biomimetic composite hydrogel. Cells grow and proliferate well in 3D composite hydrogels with excellent cell viability. When the cells undergo cancerization or microbial infection during the 3D culture, the addition of the luminol luminescence system can cause a strong bioluminescence resonance energy transfer (BRET) process to produce highly active reactive oxygen species (ROS) in 3D culture and kill the cancer cells and pathogenic microorganism effectively. Utilizing the BRET process in 3D composite biomimetic hydrogels provides an efficient antibacterial and anticancer approach in 3D culture to overcome the light-penetration limitation.

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Constitutive Activation of STAT3 in Myeloma Cells Cultured in a Three-Dimensional, Reconstructed Bone Marrow Model

Cited by 3 publications

References 33 publications

Novel Interleukin-6 Inducible Gene PDZ-Binding Kinase Promotes Tumor Growth of Multiple Myeloma Cells

Novel Interleukin-6 Inducible Gene PDZ-Binding Kinase Promotes Tumor Growth of Multiple Myeloma Cells

Ex Vivo Models Simulating the Bone Marrow Environment and Predicting Response to Therapy in Multiple Myeloma

Oligo (p-Phenylene Vinylene)/Polyisocyanopeptide Biomimetic Composite Hydrogel-Based Three-Dimensional Cell Culture System for Anticancer and Antibacterial Therapeutics

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