Cancer-associated fibroblasts shape the formation of budding cancer cells at the invasive front of human colorectal cancer

Sep 23, 2026

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The formation of budding cancer cells at solid-tumor invasive fronts represents an early metastasis step, yet the underlying mechanisms remain incompletely resolved. Using spatial molecular imaging on colorectal tumors, researchers disentangle cancer-cell–tumor-microenvironment interactions with a 1000-plex gene panel. Cancer clusters show clonal evolution, but budding-cell–containing clusters display distinct peripheral localization, frequent contact with cancer-associated fibroblasts (CAFs), and broad gene-expression shifts. These changes primarily relate to EMT, extracellular-matrix remodeling, migration, and an 11-gene metastasis-associated signature linked to inferior outcomes.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Metastasis and tumor budding

Role of the tumor microenvironment

communications biology Article | A Nature Portfolio journal | | | | --- | --- | --- | | [https://doi.org/10.1038/s42003-025-08799-x](https://doi.org/10.1038/s42003-025-08799-x) | | | | Cancer-associated ﬁ broblasts shape the formation of budding cancer cells at the invasive front of human colorectal cancer
Check for updates | | | | Juan L. García-Rodríguez 1 , Ulrik Korsgaard 2,3,4, Stine M. Vissing1, Thea Petersen Paasch 1, Mariana Semenova1, Simon L. Vendelbo1, Eva F. Jensby 5,6, Hannah L. Williams 7,
Paul Vinu Salachan 5,6, Camilla Blunk Brandt 1,8, Jacob Hanimann 7, Lin Lin 1,8, Inti Zlobec7, Karina D. Sørensen 5,6, Jørgen Kjems9,10, Henrik Hager4,5 & Lasse S. Kristensen 1 | | | | The formation of budding cancer cells at the invasive front of solid tumors is one of the ﬁrst steps of metastasis. However, this process is still incompletely elucidated. Here, we used spatial molecular imaging to disentangle the complex interactions between cancer cells and the tumor microenvironment at the invasive front of colorectal tumors. Employing a 1000-plex gene panel, we deﬁned all major cell types in tumors and adjacent normal tissue with accurate spatial information. Individual cancer cell clusters were located together, consistent with an expected mutation-and epigenetic-driven clonal evolution. However, cancer cell clusters encompassing budding cells exhibited a markedly different spatial distribution as they also contained cells that were scattered around the periphery of the main cancer cell masses. Moreover, these cells were frequently in contact with cancer-associated ﬁbroblasts (CAFs) and underwent broad gene expression changes, mainly related to epithelial-mesenchymal transition (EMT), remodeling of the extracellular matrix (ECM), and migration. In addition, we deﬁned an 11-gene signature (TYK2 , IL2RG, KRT17, HLA-B , NPPC, WIF1 , IL32 , B2M, CCND1 , CRIP1 , ITGB1), which characterizes cancer cells en route to metastasis and is associated with inferior outcomes. Collectively, our ﬁndings suggest that CAFs induce pro-invasive gene expression changes involved in EMT, ECM remodeling, and migration. | | | | The development of distant metastases accounts for most cancer-related deaths as surgical removal of metastatic lesions is often not possible or warranted due to a wider systemic spread of cancer cells in late-stage disease1. The metastatic process consists of several discrete steps, including local invasion, entry into lymphatic and/or blood vessels, extravasation into another tissue and outgrowth at the distant site2. In several solid tumors, including colorectal cancer, the sprouting of cancer cells at the invasive front (or tumor budding) of early-stage primary tumors is associated with disease progression3. Budding cells are usually deﬁned as single cancer cells or small clusters of up to four cancer cells that are isolated from the main part of the tumor and their presence inpatients with stage II colon cancer is increasingly being considered as a | poor prognostic marker that may, along with other high-risk factors, justify the consideration of adjuvant chemotherapy4.
Budding cells are hypothesized to undergo a process known as epithelial-mesenchymal transition (EMT), which is characterized by increased expression of mesenchymal markers like vimentin and decreased expression of epithelial markers. During EMT a loss or downregulation of cell–cell adhesion molecules like E-cadherin and EpCAM together with cytoskeletal rearrangements, leads to increased cell motility and tissue invasion5,6. In addition, budding cells often have an increased expression of stem cell markers, gain the capacity to degrade the extracellular matrix, and become more resistant to apoptosis7. Cancer associated ﬁbroblasts (CAFs) within the tumor microenvironment | | 1Department of Biomedicine, Aarhus University,Aarhus, Denmark. 2Department of Clinical Pathology, Lillebaelt Hospital, University Hospital of Southern Denmark, V

FAQs

Why is tumor budding important in colorectal cancer?

Tumor budding at the invasive front is linked to disease progression and is considered a poor prognostic marker in stage II colon cancer.

How do CAFs influence budding cancer cell formation?

CAFs induce pro-invasive gene-expression programs in budding cancer cells, particularly involving EMT, extracellular-matrix remodeling, and migration.

What technology was used to analyze the tumor invasive front?

Spatial molecular imaging was used to simultaneously measure 1,000 RNA molecules and profile transcriptomic changes in individual cells across tumor and adjacent tissue.

Sep 23, 2026

Uploaded by Elsa