TGF-Beta-Activated Cancer-Associated Fibroblasts Limit Cetuximab Efficacy in Preclinical Models of Head and Neck Cancer

Abstract

Most head and neck cancer (HNC) patients are resistant to cetuximab, an antibody against the epidermal growth factor receptor. Such therapy resistance is known to be mediated, in part, by stromal cells surrounding the tumor cells; however, the mechanisms underlying such a resistance phenotype remain unclear. To identify the mechanisms of cetuximab resistance in an unbiased manner, RNA-sequencing (RNA-seq) of HNC patient-derived xenografts (PDXs) was performed. Comparing the gene expression of HNC-PDXs before and after treatment with cetuximab indicated that the transforming growth factor-beta (TGF-beta) signaling pathway was upregulated in the stromal cells of PDXs that progressed on cetuximab treatment (CetuximabProg-PDX). However, in PDXs that were extremely sensitive to cetuximab (CetuximabSen-PDX), the TGF-beta pathway was downregulated in the stromal compartment. Histopathological analysis of PDXs showed that TGF-beta-activation was detected in cancer-associated fibroblasts (CAFs) of CetuximabProg-PDX. These TGF-beta-activated CAFs were sufficient to limit cetuximab efficacy in vitro and in vivo. Moreover, blocking the TGF-beta pathway using the SMAD3 inhibitor, SIS3, enhanced cetuximab efficacy and prevented the progression of CetuximabProg-PDX. Altogether, our findings indicate that TGF-beta-activated CAFs play a role in limiting cetuximab efficacy in HNC.

Index of Cancer-Associated Fibroblasts Is Superior to the Epithelial–Mesenchymal Transition Score in Prognosis Prediction

“…We were aware that several obvious caveats are inherent to the NOG xenograft study, including the fact that the lack of complete immune systems and human orthologous genes might not be entirely functional in mice. Through the literature search, we chose the TGFβ signaling pathway for further in-depth study since it is evolutionarily conserved in humans and mice [ 16 ], and has been repeatedly documented in head and cancer pathogenesis [ 18 , 32 , 33 , 34 , 35 ]. First, we consulted the single-cell RNA-seq dataset GSE103322, comprising ~6000 malignant and non-malignant cells from 18 OSCC tissues, for the cell types that express genes of our interest.…”

“…In the phase I clinical trial EDALIN, 3 of 12 patients with metastatic triple-negative breast cancer who received combined chemotherapies of stroma (sonidegib) and tumor (docetaxel) showed clinical benefits, including one patient experiencing a complete response [ 45 ]. Recently, in five head and neck patient-derived xenograft mouse models, Yegodayev et al [ 18 ] demonstrated that TGFβ-activated stromal CAFs limited cetuximab efficacy in vivo, which can be improved by an SMAD3 inhibitor, SIS3. Given these promising results, comprehensive consensuses about the roles of CAFs in tumorigenesis are emerging [ 15 , 46 ].…”

“…The comparative genomic loci of most human and mouse TGFβ axis genes, including TGFB1–3, TGFBR1–3, and TGFBI, were mapped ~20 years ago [ 16 ], which paved the way for numerous functional studies of individual TGFβ genes in tumor biology. Importantly, this pathway comprises multiple targets attributable to therapeutic resistance [ 17 , 18 ], linking its importance to clinics.…”

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…Physiologically, natural gastric stroma contains only a few fibroblasts, and those are mainly myofibroblasts. The number of fibroblasts is significantly increased in tissues affected by inflammation or neoplasm [228][229][230][231]. In a gastric cancer microenvironment, macrophages via interaction with mesenchymal stem cells induce differentiation of cancer-associated fibroblasts (CAFs) [232][233][234].…”

The Biology of Myxofibrosarcoma: State of the Art and Future Perspectives

“…The roles of TGF-β in remodeling the tumor microenvironment, by suppressing T-cell differentiation and activity, inducing fibrosis and angiogenesis, have been extensively characterized [77]. TGF-β also appears to have a role in chemotherapy resistance, as reported in several tumors including breast cancer and squamous cell carcinoma [78-80].…”