Autophagic secretion of HMGB1 from cancer-associated fibroblasts promotes metastatic potential of non-small cell lung cancer cells via NFκB signaling

Abstract

Tumor progression requires the communication between tumor cells and tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are major components of stromal cells. CAFs contribute to metastasis process through direct or indirect interaction with tumor cells; however, the underlying mechanism is largely unknown. Here, we reported that autophagy was upregulated in lung cancer-associated CAFs compared to normal fibroblasts (NFs), and autophagy was responsible for the promoting effect of CAFs on non-small cell lung cancer (NSCLC) cell migration and invasion. Inhibition of CAFs autophagy attenuated their regulation on epithelial–mesenchymal transition (EMT) and metastasis-related genes of NSCLC cells. High mobility group box 1 (HMGB1) secreted by CAFs mediated CAFs’ effect on lung cancer cell invasion, demonstrated by using recombinant HMGB1, HMGB1 neutralizing antibody, and HMGB1 inhibitor glycyrrhizin (GA). Importantly, the autophagy blockade of CAFs revealed that HMGB1 release was dependent on autophagy. We also found HMGB1 was responsible, at least in part, for autophagy activation of CAFs, suggesting CAFs remain active through an autocrine HMGB1 loop. Further study demonstrated that HMGB1 facilitated lung cancer cell invasion by activating the NFκB pathway. In a mouse xenograft model, the autophagy specific inhibitor chloroquine abolished the stimulating effect of CAFs on tumor growth. These results elucidated an oncogenic function for secretory autophagy in lung cancer-associated CAFs that promotes metastasis potential, and suggested HMGB1 as a novel therapeutic target.

Multi-Omics Characterization of Tumor Microenvironment Heterogeneity and Immunotherapy Resistance Through Cell States–Based Subtyping in Bladder Cancer

“…The SCNAs of four subtypes in the TCGA-BLCA cohort were analyzed and compared, and the result showed that the four subtypes had different SCNAs ( Figure 6A ). The 13q12.3 amplification in C1 contained HMGB1, which could promote the development of MDSC and the metastasis of cancer cells ( Gorgulho et al, 2019 ; Ren et al, 2021 ). FSCN1 amplification at 7p22.1, Gab2 amplification at 11q14.1, and CD44 amplification at 11p13 were also associated with promoting tumor invasion ( Ke et al, 2007 ; Li et al, 2018 ; Rohani et al, 2019 ) and inducing tumor resistance to radiotherapy ( Li et al, 2021 ), suggesting that patients with C1 had high immune suppression, active EMT, and may not be suitable for radiation therapy.…”

Systematic analysis of expression profiles of HMGB family members for prognostic application in non-small cell lung cancer

“…HMGB1 plays a significant role in many diseases, including autoimmune diseases, infectious diseases, inflammatory diseases, and cancer ( Kang et al, 2013 ; Tripathi et al, 2019 ). In cancer, HMGB1 plays dual roles as both a pro-cancer and an anti-cancer factor by regulating multiple cellular processes, including proliferation, angiogenesis, and invasion ( Wu et al, 2018 ; Ren et al, 2021 ). HMGB1 has been shown to enhance tumor growth, angiogenesis, and metastasis of a variety of cancers, including breast cancer, prostate cancer, colorectal cancer, and lung cancer ( Zhang J et al, 2014 ; Zhang L et al, 2014 ; Meng et al, 2014 ; Süren et al, 2014 ; Liu et al, 2015 ; Sun et al, 2015 ; Ren et al, 2021 ).…”

“…In cancer, HMGB1 plays dual roles as both a pro-cancer and an anti-cancer factor by regulating multiple cellular processes, including proliferation, angiogenesis, and invasion ( Wu et al, 2018 ; Ren et al, 2021 ). HMGB1 has been shown to enhance tumor growth, angiogenesis, and metastasis of a variety of cancers, including breast cancer, prostate cancer, colorectal cancer, and lung cancer ( Zhang J et al, 2014 ; Zhang L et al, 2014 ; Meng et al, 2014 ; Süren et al, 2014 ; Liu et al, 2015 ; Sun et al, 2015 ; Ren et al, 2021 ). In contrast, Kang et al (2013) and Luan et al (2017) reported that HMGB1 acts as a tumor suppressor in pancreatic cancer and endometrial carcinoma ( Tang et al, 2010 ; Zuo et al, 2014 ).…”

DataSheet4.PDF

“…HMGB1 plays a significant role in many diseases, including autoimmune diseases, infectious diseases, inflammatory diseases, and cancer (Kang et al, 2013;Tripathi et al, 2019). In cancer, HMGB1 plays dual roles as both a pro-cancer and an anti-cancer factor by regulating multiple cellular processes, including proliferation, angiogenesis, and invasion (Wu et al, 2018;Ren et al, 2021). HMGB1 has been shown to enhance tumor growth, angiogenesis, and metastasis of a variety of cancers, including breast cancer, prostate cancer, colorectal cancer, and lung cancer Zhang L et al, 2014;Meng et al, 2014;Süren et al, 2014;Liu et al, 2015;Sun et al, 2015;Ren et al, 2021).…”

“…In cancer, HMGB1 plays dual roles as both a pro-cancer and an anti-cancer factor by regulating multiple cellular processes, including proliferation, angiogenesis, and invasion (Wu et al, 2018;Ren et al, 2021). HMGB1 has been shown to enhance tumor growth, angiogenesis, and metastasis of a variety of cancers, including breast cancer, prostate cancer, colorectal cancer, and lung cancer Zhang L et al, 2014;Meng et al, 2014;Süren et al, 2014;Liu et al, 2015;Sun et al, 2015;Ren et al, 2021). In contrast, Kang et al (2013) and Luan et al (2017) reported that HMGB1 acts as a tumor suppressor in pancreatic cancer and endometrial carcinoma (Tang et al, 2010;Zuo et al, 2014).…”