Activation of CD44 signaling in leader cells induced by tumor-associated macrophages drives collective detachment in luminal breast carcinomas

Abstract

Collective detachment of cancer cells at the invading front could generate efficient metastatic spread. However, how cancer cell clusters shed from the leading front remains unknown. We previously reported that the dynamic expression of CD44 in breast cancers (BrCas) at collectively invading edges was associated with tumor-associated macrophages (TAMs). In this study, we first observed that the highly expressed CD44 (CD44high) cancer cell clusters were located in the BrCa circulating vessels, accompanied by CD206+ TAMs. Next, we identified that the cancer cell clusters can be converted to an invasive CD44high state which was induced by TAMs, thus giving rise to CD44-associated signaling mediated cohesive detachment. Then, we showed that disrupting CD44-signaling inhibited the TAMs triggered cohesive detaching using 3D organotypic culture and mouse models. Furthermore, our mechanistic study showed that the acquisition of CD44high state was mediated by the MDM2/p53 pathway activation which was induced by CCL8 released from TAMs. Blocking of CCL8 could inhibit the signaling cascade which decreased the CD44-mediated cohesive detachment and spread. Our findings uncover a novel mechanism underlying collective metastasis in BrCas that may be helpful to seek for potential targets.

The inhibition of pancreatic cancer progression by K-Ras-overexpressing mesenchymal stem cell-derived secretomes

“…The elevated level of MSN in PI3K-activated MSC-derived CM was consistent with its tumor-suppressive actions on PANC1 and Pa03C pancreatic cancer cells. Immunoprecipitation supported MSN’s interaction with CD44, a non-kinase transmembrane glycoprotein 40 . CD44 is overexpressed in many types of cancer including pancreatic cancer 41 , and its high expression level in pancreatic cancer led to poor survival (p = 0.0045).…”

Hybrid cancer stem cells utilise vascular tracks for collective streaming invasion in a metastasis-on-a-chip device

“…CD44 is a transmembrane glycoprotein that is a CSC marker in OSCC (Prince et al, 2007). Other studies have also demonstrated the presence of CD44 +ve cells at the edge of collective invasive masses (Gao et al, 2022, Wolf et al, 2020. For instance, showed that the invasive front of breast tumours exhibits a hybrid EMT phenotype, with high expression of CD44.…”