TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations

Dodhiawala, Paarth B.; Khurana, Namrata; Zhang, Daoxiang; Cheng, Yeung Leung; Li, Lin; Wei, Qing; Seehra, Kuljeet; Jiang, Hongmei; Grierson, Patrick; Wang‐Gillam, Andrea; Lim, Kian Huat

doi:10.1172/jci137660

Cited by 23 publications

(33 citation statements)

References 63 publications

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“… 108 Targeting the NF-κB pathway through suppressing Interleukin-1 receptor associated kinase 4 (IRAK4) sensitizes PDAC cells to genotoxic stress and simultaneously lowers the ability of CAFs to deposit collagen and foster tumor fibrosis, leading to improved response to chemotherapy. 54 , 92 , 183 …”

Section: Therapeutic Targeting Of Pdac Stroma: Recent Lessonsmentioning

confidence: 99%

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Bulle

Lim

2020

Sig Transduct Target Ther

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115

123

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Novel effective treatment is direly needed for patients with pancreatic ductal adenocarcinoma (PDAC). Therapeutics that target the driver mutations, especially the KRAS oncoprotein and its effector cascades, have been ineffective. It is increasing clear that the extensive fibro-inflammatory stroma (or desmoplasia) of PDAC plays an active role in the progression and therapeutic resistance of PDAC. The desmoplastic stroma is composed of dense extracellular matrix (ECM) deposited mainly by the cancer-associated-fibroblasts (CAFs) and infiltrated with various types of immune cells. The dense ECM functions as a physical barrier that limits tumor vasculatures and distribution of therapeutics to PDAC cells. In addition, mounting evidence have demonstrated that both CAFs and ECM promote PDAC cells aggressiveness through multiple mechanisms, particularly engagement of the epithelial-mesenchymal transition (EMT) program. Acquisition of a mesenchymal-like phenotype renders PDAC cells more invasive and resistant to therapy-induced apoptosis. Here, we critically review seminal and recent articles on the signaling mechanisms by which each stromal element promotes EMT in PDAC. We discussed the experimental models that are currently employed and best suited to study EMT in PDAC, which are instrumental in increasing the chance of successful clinical translation.

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Section: Therapeutic Targeting Of Pdac Stroma: Recent Lessonsmentioning

confidence: 99%

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Bulle

Lim

2020

Sig Transduct Target Ther

Self Cite

115

123

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“…In addition, expression of TLR9 in PDAC cells can be further induced following DNA damage caused by chemotherapy, particularly irinotecan, leading to activation of IRAK4 and TPL2 kinases and the downstream NF-κB and MAPK pathways. These events sustain cellular survival to allow DNA damage repair [ 81 ]. In addition, TLR9 stimulation promotes vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) production, as well as expression of the anti-apoptotic protein Bcl-xL [ 82 ].…”

Section: Mechanisms That Activate the Nf-κb Pathway In Pdacmentioning

confidence: 99%

“…In addition, TPL2 has also been shown to phosphorylate RELA/p65 NF-κB subunit at its Ser276 residue, MKK4/SEK1 (proximal kinase of JNK) and MKK3/6 (proximal kinase of p38α) in fibroblasts, and macrophages stimulated with TNF-α or LPS [ 133 , 141 , 142 ]. In PDAC cells, TPL2 is activated via a KRAS-MAPK driven IL-1β autocrine signaling loop [ 81 ]. In this setting, inhibition of TPL2 suppresses both MAPK and NF-κB pathways.…”

Section: Mechanisms That Activate the Nf-κb Pathway In Pdacmentioning

confidence: 99%

“…Contribution of the RAF-MEK-ERK cascade to the NF-κB cascade is indirect and mediated through autocrine IL-1β production. Through the RAF-MEK-ERK cascade, the KRAS oncoprotein markedly upregulates production of IL-1β, which, in an autocrine manner, engages the IL-1R-IRAK4-TPL2 axis to activate the canonical NF-κB pathway and further reinforces MEK-ERK activity [ 81 ]. Importantly, ablation of IRAK4 completely blocks KRAS-induced transformation and tumorigenesis [ 87 ].…”

Section: Intricate Crosstalk Between the Kras And Nf-κb Pathwaysmentioning

confidence: 99%

“…Interim results showed CA-4948 at 200 mg twice daily to be generally well tolerated and showing preliminary efficacy [ 161 ] (NCT03328078). The combination of IRAK4 inhibitors with chemotherapy is supported by preclinical studies [ 49 , 81 , 162 ] and should be advanced into clinical trials.…”

Section: Therapeutic Targeting Of the Nf-ĸb Pathway In Pdacmentioning

confidence: 99%

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Deciphering the Role of Innate Immune NF-ĸB Pathway in Pancreatic Cancer

Khurana

Dodhiawala

Bulle

et al. 2020

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with no effective treatment option. A predominant hallmark of PDAC is the intense fibro-inflammatory stroma which not only physically collapses vasculature but also functionally suppresses anti-tumor immunity. Constitutive and induced activation of the NF-κB transcription factors is a major mechanism that drives inflammation in PDAC. While targeting this pathway is widely supported as a promising therapeutic strategy, clinical success is elusive due to a lack of safe and effective anti-NF-κB pathway therapeutics. Furthermore, the cell type-specific contribution of this pathway, specifically in neoplastic cells, stromal fibroblasts, and immune cells, has not been critically appraised. In this article, we highlighted seminal and recent literature on molecular mechanisms that drive NF-κB activity in each of these major cell types in PDAC, focusing specifically on the innate immune Toll-like/IL-1 receptor pathway. We reviewed recent evidence on the signaling interplay between the NF-κB and oncogenic KRAS signaling pathways in PDAC cells and their collective contribution to cancer inflammation. Lastly, we reviewed clinical trials on agents that target the NF-κB pathway and novel therapeutic strategies that have been proposed in preclinical studies.

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Photocurrent‐Directed Immunoregulation Accelerates Osseointegration through Activating Calcium Influx in Macrophages

Zhu,

Wang,

et al. 2024

Adv Funct Materials

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Early osteoimmune microenvironment disorder at the interface between bone and implant can lead to implant loosening, which prolongs patient convalescence, exacerbates postoperative complications, and potentially results in implant failure. The timely regulation of macrophages primarily orchestrates the entire long‐term regeneration process. Here, it is proposed to precisely direct macrophage polarization using localized photoelectrical signals generated by an excitable surface in response to remote stimulation via near‐infrared light (NIR). The photocurrent generated from the n–n heterojunction between calcium titanate (CaTiO3) and defective titanium dioxide (TiO2‐Vo) on the excitable surface can accurately direct macrophage polarization, suppressing acute inflammation at the early stage of post‐implantation and establishing a favorable osteoimmune microenvironment that promotes bone‐to‐implant integration. Mechanistic study reveals that photoelectric signals initiate increased calcium influx via voltage‐gated calcium ion channels, subsequently modulating calcium/calmodulin‐dependent protein kinase kinase 2 (Camkk2) and calcium/calmodulin‐dependent protein kinase I (Camk1) expression to regulate macrophage polarization. This optimization of the osteoimmune microenvironment results in enhanced mesenchymal stem cells (MSCs) recruitment and osteogenesis, ultimately accelerating bone‐to‐implant integration within 14 days post‐implantation. This research presents a novel method for adjusting in vivo spatiotemporal immune responses through the use of noninvasive and externally‐controlled targeted stimulations.

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TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations

Cited by 23 publications

References 63 publications

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Deciphering the Role of Innate Immune NF-ĸB Pathway in Pancreatic Cancer

Photocurrent‐Directed Immunoregulation Accelerates Osseointegration through Activating Calcium Influx in Macrophages

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