CD10⁺GPR77⁺ Cancer-Associated Fibroblasts Promote Chemoresistance

Carcinoma-associated fibroblasts (CAF) are heterogeneous stromal cells in the tumor microenvironment thought to promote tumor progression. However, targeting CAFs promoted tumor progression in pancreatic cancer, suggesting that CAFs may have both tumor-promoting and tumor-suppressing roles. Su, Chen, Yao, and colleagues sought to identify specific cancer-promoting CAF subsets that might represent therapeutic targets. Analysis of paired tumor samples from patients with breast cancer before and after neo-adjuvant chemotherapy revealed no difference in the number of CAFs in chemosensitive versus chemoresistant patients. Microarray analysis of RNA from CAFs from 7 sensitive and 7 resistant patients found that the cell-surface markers CD10 and GPR77 were upregulated in the CAFs from chemoresistant tumors, a finding that was validated in an additional 24 patients. In patients with breast cancer or non–small cell lung cancer, high levels of CD10⁺GPR77⁺ CAFs were associated with chemoresistance and poor survival. In a breast cancer xenograft model, CD10⁺GPR77⁺ CAFs were themselves chemoresistant and also induced conferred chemoresistance to the tumor cells in their microenvironment. CD10⁺GPR77⁺ CAFs secreted IL6 and IL8, creating a niche that promoted cancer stem cell (CSC) chemoresistance and survival, and thereby enhancing the engraftment of breast cancer patient-derived xenografts (PDX). Mechanistically, GPR77 induced p65 phosphorylation that promoted P300-mediated p65 acetylation to drive persistent NF-κB activation that maintained the phenotypes and functions of CD10⁺GPR77⁺ CAFs. Inhibiting GPR77 with a neutralizing antibody blocked the establishment of breast cancer PDXs, and, in established PDXs, anti-GPR77 enhanced the efficacy of chemotherapy. In addition to identifying a CD10⁺GPR77⁺ tumor-promoting subset of CAFs, these findings suggest that targeting CD10⁺GPR77⁺ CAFs (as with an anti-GPR77 antibody) may suppress breast tumorigenesis and sensitize tumors to chemotherapy.

Su S, Chen J, Yao H, Liu J, Yu S, Lao L, et al. CD10⁺GPR77⁺ cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 2018;172:841–56.e16.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.