Abstract
Tumor budding has been found to be of prognostic significance for several cancers, including colorectal cancer (CRC). Additionally, the molecular classification of CRC has led to the identification of different immune microenvironments linked to distinct prognosis and therapeutic response. However, the association between tumor budding and the different molecular subtypes of CRC and distinct immune profiles have not been fully elucidated. This study focused, firstly, on the validation of derived xenograft models (PDXs) for the evaluation of tumor budding and their human counterparts and, secondly, on the association between tumor budding and the immune tumor microenvironment by the analysis of gene expression signatures of immune checkpoints, Toll-like receptors (TLRs), and chemokine families. Clinical CRC samples with different grades of tumor budding and their corresponding PDXs were included in this study. Tumor budding grade was reliably reproduced in early passages of PDXs, and high-grade tumor budding was intimately related with a poor-prognosis CMS4 mesenchymal subtype. In addition, an upregulation of negative regulatory immune checkpoints (PDL1, TIM-3, NOX2, and IDO1), TLRs (TLR1, TLR3, TLR4, and TLR6), and chemokine receptors and ligands (CXCR2, CXCR4, CXCL1, CXCL2, CXCL6, and CXCL9) was detected in high-grade tumor budding in both human samples and their corresponding xenografts. Our data support a close link between high-grade tumor budding in CRC and a distinctive immune-suppressive microenvironment promoting tumor invasion, which may have a determinant role in the poor prognosis of the CMS4 mesenchymal subtype. In addition, our study demonstrates that PDX models may constitute a robust preclinical platform for the development of novel therapies directed against tumor budding in CRC.
Highlights
Tumor budding has recently received much attention in the setting of progression and invasion in several malignancies including colorectal cancer (CRC)
High-grade tumor budding is established as an independent prognostic factor since it has been associated with shorter disease-free survival (DFS) and overall survival (OS) in several types of cancer [2,3,4]
We examined early passages of CRC Patient-derived xenografts (PDXs) as potential models to analyze tumor budding and, secondly, we elucidated a link between high-grade budding and CMS4 subtype and specific signatures of immune evasion
Summary
Tumor budding has recently received much attention in the setting of progression and invasion in several malignancies including colorectal cancer (CRC). High-grade tumor budding is established as an independent prognostic factor since it has been associated with shorter disease-free survival (DFS) and overall survival (OS) in several types of cancer [2,3,4]. It is widely believed that tumor buds provide the histological basis for invasion and metastasis, but it is still a matter of controversy if it is directly related with the epithelial–mesenchymal transition (EMT) [5, 6]. High-grade tumor budding has been inversely correlated with the presence of immune infiltrate at the invasive front. An overexpression of stem-cell related genes as ZEB1, ZEB2, DES, and VIM, and the activation of both WNT and TGFβ signaling, has been demonstrated to be expressed in tumor buds [7,8,9]
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