Lin28B-high breast cancer cells promote immune suppression in the lung pre-metastatic niche via exosomes and support cancer progression

Abstract

The formation of pre-metastatic niche is a key step in the metastatic burden. The pluripotent factor Lin28B is frequently expressed in breast tumors and is particularly upregulated in the triple negative breast cancer subtype. Here, we demonstrate that Lin28B promotes lung metastasis of breast cancer by building an immune-suppressive pre-metastatic niche. Lin28B enables neutrophil recruitment and N2 conversion. The N2 neutrophils are then essential for immune suppression in pre-metastatic lung by PD-L2 up-regulation and a dysregulated cytokine milieu. We also identify that breast cancer-released exosomes with low let-7s are a prerequisite for Lin28B-induced immune suppression. Moreover, Lin28B-induced breast cancer stem cells are the main sources of low-let-7s exosomes. Clinical data further verify that high Lin28B and low let-7s in tumors are both indicators for poor prognosis and lung metastasis in breast cancer patients. Together, these data reveal a mechanism by which Lin28B directs the formation of an immune-suppressive pre-metastatic niche.

Breast Cancer Metastasis: Mechanisms and Therapeutic Implications

“…Lin28, an RNA-binding protein, is one of the master regulators of embryonic stem cell self-renewal that correlates with clinical tumor grade and the terminal metastasis of breast cancer [ 50 ]. In the MMTV-PyMT mouse model, Lin28B did not affect the primary tumor growth but promoted the development of lung metastases [ 54 ], suggesting that the ability of cancer cells to self-renew can promote distant metastasis in breast cancer. IL-6 secreted from differentiated cancer cells supports CSC survival, metastasis, and treatment resistance in breast cancer [ 55 , 56 ].…”

Breast Cancer-Delivered Exosomal miRNA as Liquid Biopsy Biomarkers for Metastasis Prediction: A Focus on Translational Research with Clinical Applicability

“…By suppressing the local immunity, tumor-derived exosomes can distantly support the colonization of the pre-metastatic site. Let-7 downregulation due to its binding by Lin28 allowed the building of an immune-suppressive pre-metastatic niche in the lungs, by enabling neutrophil recruitment and N2 conversion in vivo [ 87 ]. Let-7 restoration in exosomes was able to abolish the immunosuppressive and pro-metastatic effects of breast cancer cell-derived exosomes, highlighting its extensive inhibitory role in tumor progression [ 87 , 88 ].…”

“…Let-7 downregulation due to its binding by Lin28 allowed the building of an immune-suppressive pre-metastatic niche in the lungs, by enabling neutrophil recruitment and N2 conversion in vivo [ 87 ]. Let-7 restoration in exosomes was able to abolish the immunosuppressive and pro-metastatic effects of breast cancer cell-derived exosomes, highlighting its extensive inhibitory role in tumor progression [ 87 , 88 ]. Another important factor in the development of the pre-metastatic niche is the metabolic reprogramming of the resident cells.…”

Roles of tumor-associated neutrophils in tumor metastasis and its clinical applications

“…Frontiers in Cell and Developmental Biology frontiersin.org Dormant cancer cells are characterized by increased p38 mitogen-activated protein kinase (p38 MAPK) and decreased extracellular signal-regulated kinase 1/2 (ERK1/2) activity; the p38 MAPK high /ERK low phenotype is commonly used as a marker of dormancy (Recasens and Munoz, 2019).…”