Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during clinical latency

Abstract

Although thousands of breast cancer cells disseminate and home to bone marrow until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. To identify signals that support survival or outgrowth in patients, we profile rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identify IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lack membranous IL6 receptor expression and mechanistic dissection reveals IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals is found to be niche-dependent as bone marrow stromal and endosteal cells down-regulate gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation renders cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we find PIK3CA mutations highly associated with late-stage metastatic cells while being extremely rare in early DCCs. Our data suggest that the initial steps of metastasis formation are often not cancer cell-autonomous, but also depend on microenvironmental signals.

Bone metastasis: mechanisms, therapies, and biomarkers

“…Thus, these clinical observations provide strong evidence of tumor dormancy in the bone marrow. However, DTCs isolated from the bone marrow of non-metastatic patients with cancer (breast, prostate, melanoma) fail to generate tumor xenografts in immunodeficient mice (364). Consequently, only tumor cell lines derived from overt metastases from patients with advanced cancer (breast, prostate) have been used in animal models to study tumor dormancy in bone (31,46,117,119,163,177,267,320,381,382).…”

“…In addition, independently of the hormone receptor status or breast cancer subtype, CXCL-12 triggers activation of a Src-dependent AKT signaling pathway by binding to CXCR-4, enhancing the survival of breast cancer cells in the bone marrow (387). Of note, Werner-Klein et al (364) performed single-cell RNA-sequencing analysis of DTCs isolated from the bone marrow of non-metastatic breast cancer patients (n=30 DTCs; patients) and found that mRNA expression of the IL-6 signal transducing unit gp130 (IL6ST) is strongly enriched in these cells, whereas the mRNA of the IL-6 binding receptor alpha chain CD126 (IL6RA) is absent. In the absence of CD126, the IL-6 signaling pathway can be activated in trans through the binding of IL-6 to the soluble form of CD126 (sIL6RA) prior to binding to gp130.…”

“…Both IL-6 and sIL6RA are abundant in the bone marrow, and IL-6 trans-signaling through the PI3K/AKT pathway can be activated in tumor cells (364). However, the endosteal niche renders DTCs unresponsive to IL-6 trans-signaling (364).…”

Leveraging Single-Cell Approaches in Cancer Precision Medicine

“…This study found that PIK3CA variants in the single cells of bone metastases were more diverse from the variants found in the CTCs, suggesting drug refractory states may be better reflected in the heterogenous cancer cell populations in the metastases compared to CTCs. A subsequent study of TNBCs also reported the presence of pathogenic PIK3CA mutations in the malignant single cells derived from bone marrow metastases, which were absent in primary and non-metastatic tumors [27]. Targeted scDNA-seq analysis of cell-free DNA (cfDNA) and CTCs from metastatic breast cancers, found persistent heterogeneity in pathogenic variants of PIK3CA, TP53, ESR1, and KRAS genes, that were correlated with metastatic burden and prognostic implications [28].…”

Cancer stem cells and macrophages: molecular connections and future perspectives against cancer

“…The interactions may be direct or indirect, and the effects on CSCs include chemoresistance, preservation, and the capacity to differentiate [ 161 , 162 ]. TAMs produce cytokines including milk fat globule epidermal growth factor 8 (MFG-E8); interleukin 6 (IL-6), which can activate STAT3; and the Hedgehog signaling pathway, which seems to be one of the causes of drug resistance [ 163 , 164 ]. For example, in hepatocarcinoma, IL-6 promotes the expression of CD44+, inducing tumor development [ 165 ].…”