CD10+GPR77+ Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness

Abstract

Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10GPR77 CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10GPR77 CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10GPR77 CAFs promote successful engraftment of patient-derived xenografts (PDXs), and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers and suggests that targeting the CD10GPR77 CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors.

Inter‐ and intra‐tumoural heterogeneity in cancer‐associated fibroblasts of human pancreatic ductal adenocarcinoma

“…Ikenaga et al showed the presence of two subpopulations of CAFs in human PDAC stroma (CD10‐positive and CD10‐negative), with the former having a more pro‐tumoural role. Su et al recently confirmed this finding in breast and lung cancers, and demonstrated that a subset of CD10‐positive CAFs (CD10+GPR77+) promote cancer formation and chemoresistance by sustaining cancer stemness. In contrast, we used a ‘without a priori ’ approach, based on the transcriptomic profile of primary cultures to build an assignation, and described distinct phenotypic profiles of CAF subpopulations.…”

The prognostic value of the tumor–stroma ratio is most discriminative in patients with grade III or triple‐negative breast cancer

“…An important recent finding is the identification of CD10 and GPR77 as surface markers on CAFs in breast cancer. CD10 + GPR77 + CAFs are predictive for response to chemotherapy and patient survival, particularly in breast tumors with a high grade . The authors showed that the disease‐free survival of breast cancer patients with a high CD10 + GPR77 + CAF infiltration was significantly shorter.…”

Concise Review: Targeting Cancer Stem Cells and Their Supporting Niche Using Oncolytic Viruses

“…As M2 macrophages express CD206 in hypoxic niches , a virally encoded CD206‐CD3 BiTE could potentially activate T cells in the presence of M2 type TAMs. Recent studies have shed light on the ability of CSCs to communicate with TME components such as CAFs , via exosomes and other secreted factors. A major challenge to many therapies involves overcoming CAF‐mediated effects in the TME, such as their promotion of tumor growth, angiogenesis, extracellular matrix degradation and EMT .…”

“…Recent studies have shed light on the ability of CSCs to communicate with TME components such as CAFs , via exosomes and other secreted factors. A major challenge to many therapies involves overcoming CAF‐mediated effects in the TME, such as their promotion of tumor growth, angiogenesis, extracellular matrix degradation and EMT . In recent studies, a fibroblast‐activating protein‐CD3 BiTE has been encoded in an oncolytic vaccinia virus or adenovirus to target immunosuppressive stromal cells .…”