NLRP3 activation in tumor-associated macrophages enhances lung metastasis of pancreatic ductal adenocarcinoma

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is highly malignant due to its late diagnosis and early metastasis. Lung metastasis of PDAC occurs in a significant number of diagnosed patients and represents high severity of disease and poor clinical outcome.However, the molecular regulation of lung metastasis of PDAC is still not fully understood. Tumorassociated macrophages (TAMs) have recently been found to play an important role in cancer initiation, proliferation, progression, and metastasis. The proliferation, differentiation, and polarization of macrophages has been shown to be regulated by interleukin 1β (IL-1β), which is generated by NLR family pyrin domain containing 3 (NLRP3)-induced formation of inflammasome. Herein we investigated whether NLRP3 plays a role in lung metastasis of PDAC through regulation of macrophage polarization.Methods: Gene profiles for NLRP3 (+/+) and NLRP3 (−/−) macrophages obtained from the Gene Expression Omnibus (GEO) public database were compared and analyzed for altered genes related to macrophage polarization. The regulation of macrophage polarization by NLRP3 was examined in a coculture system with naïve NLRP3 (+/+) or NLRP3 (−/−) macrophages and PDAC cells. Cell growth was analyzed by a Cell Counting Kit-8 (CCK-8) assay. Cell invasiveness and migratory potential were analyzed by transwell cell invasion assay and cell migration assay, respectively. PDAC formation and lung metastasis were analyzed in a mouse model of PDAC with and without NLRP3 knockout.Results: GEO database analysis revealed significant alteration in genes that regulate macrophage polarization in NLRP3-depleted macrophages. NLRP3-depletion in macrophages seemed to favor an M1/ M2b polarization. In vitro, the presence of NLRP3 in macrophages led to M2a/c/d TAM-like polarization when they were cocultured with PDAC cells. Conversely, NLRP3 depletion in macrophages led to M1/M2b polarization when they were cocultured with PDAC cells. NLRP3-depletion significantly inhibited tumor growth and stage progression in a mouse model of PDAC and significantly reduced the occurrence of lung metastasis.Conclusions: Our results suggested that NLRP3 activation in TAM enhanced lung metastasis of PDAC through regulation of TAM polarization.

Knockdown of ANLN inhibits the progression of lung adenocarcinoma via pyroptosis activation

“…Analysis of prognosis has revealed a lower survival rate in patients with LUAD who exhibit low expression levels of NLRP7, NLRP1, NLRP2 and nucleotide binding oligomerization domain containing 1, as well as high expression levels of caspase-6 ( 17 ). Additionally, activation of the NLRP3 inflammasome has been shown to accelerate the progression of LUAD by promoting the proliferation and metastasis of lung cancer cells ( 18 ). Conversely, downregulation of GSDMD has been demonstrated to mitigate tumor proliferation via the intrinsic mitochondrial apoptotic pathway, as well as through inhibition of EGFR/Akt signaling, and is associated with favorable prognostic outcomes in LUAD ( 19 , 20 ).…”

Predicting Prognosis and Immunotherapy Response in Multiple Cancers Based on the Association of PANoptosis-Related Genes with Tumor Heterogeneity

“…According to previous reports, cells with CASP8 mutations are resistant to exogenous agents that induce cell apoptosis, which can prevent the killing of tumor cells by T cells through FasL-Fas interactions, which is one of the immune evasion mechanisms of tumors [32,33]. The NLRP3 inflammasome is a key component of the innate immune system, and depletion of NLRP3 in macrophages is beneficial for M1/M2b polarization [34]. NLRP3 depletion significantly inhibited tumor growth and stage progression, and it also significantly reduced the occurrence of pancreatic ductal adenocarcinoma (PDAC) lung metastasis [34].…”

“…The NLRP3 inflammasome is a key component of the innate immune system, and depletion of NLRP3 in macrophages is beneficial for M1/M2b polarization [34]. NLRP3 depletion significantly inhibited tumor growth and stage progression, and it also significantly reduced the occurrence of pancreatic ductal adenocarcinoma (PDAC) lung metastasis [34]. Methylation level was most closely related to survival in LGG and ACC.…”

Targeted Therapy for Highly Desmoplastic and Immunosuppressive Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma

“…In addition, TAMs can promote tumor cell metastasis and induce therapeutic resistance. For example, NLR family pyrin domain containing 3 (NLRP3) activation induced the M2-like macrophage polarization of TAMs in a murine model of PDAC to promote cancer cell lung metastasis [78]. Therefore, targeting TAMs and their associated factors can improve PDAC therapy.…”