Progressive plasticity in colorectal cancer metastasis: a comprehensive analysis with Talk2Data

Colorectal cancer (CRC) is the third most prevalent cancer and the second leading cause of cancer-related deaths worldwide [1]. Progressive plasticity refers to the ability of cancerous cells to adapt their state, phenotype, and molecular characteristics in response to environmental stimuli. This plasticity significantly contributes to the metastasis of cancerous cells, their survival in distant organs, and the development of resistance to therapies. Understanding progressive plasticity in CRC metastasis is crucial for developing more effective treatments, preventing metastatic progression, and improving patient survival outcomes.

This blog, inspired by a recent publication in Nature [2], presents key findings related to plasticity during CRC metastasis derived from an extensive analysis using BioTuring’s Talk2Data platform. The aim is to explore whether the findings from CRC single-cell studies in the Talk2Data database align with those reported in the study. Our analysis within Talk2Data focuses on CRC studies, encompassing a combined dataset of 883,100 cells (as of January 2025). The following figures have been exported from Talk2Data to illustrate our findings. A mini-webinar discussing this work is available on the BioTuring Team’s channel.

1. Metastatic cells lose intestinal cell identities

The database-wide analysis reveals that metastatic cells exhibit a trend of decreased expression of intestinal stem cell (ISC)-related gene programs when compared to their primary tumour counterparts. This includes downregulation of genes associated with WNT signaling (LGR5, EPHB2, ASCL2, and TCF7), embryonic development (BMP7, SOX4, and CYP2W1), and stress response (MTOR) (Figure 1). In essence, ISC programs are diminished in metastatic tumours, suggesting that CRC cells progressively lose their intestinal cell identities during the process of metastasis.

2. Metastatic cells undergo non-canonical differentiation

The data demonstrate a progressive loss of canonical intestinal lineage identity. The modules associated with canonical intestinal states include genes characteristic of ISCs (such as LGR5 and ASCL2), differentiated absorptive markers (like FABP2 and KRT20), and secretory genes (including TFF3 and TFF1). Notably, CRC cells co-express programs related to both absorptive and secretory intestinal cell types, along with ISC-related genes (Figure 2). In metastatic lesions, the expression levels of the canonical differentiation program are lower than those observed in primary tumours, indicating that the expression of non-canonical modules is linked to the metastatic process. Downregulation of the secreted trefoil factor family 3 (TFF3) was reported to be involved in CRC progression and intestinal mucosal repair [3].

3. Tumour cells lose gene correlation structure

There is a notable deterioration in gene correlation structure within CRC primary tumour cells (Figure 3). This suggests that primary tumour cells may gradually lose their distinct cell identities and progress toward metastatic stages.

4. PROX1 represses non-canonical differentiation

The homeobox transcription factor PROX1 functions as a repressor of non-canonical differentiation, facilitating the redifferentiation of cells to canonical intestinal fates. In metastatic cells expressing PROX1, there is an entry into an injured state characterized by elevated expression of EMP1 and L1CAM genes, which are markers for CRC metastasis-initiating cells, along with TACSTD2, CD70, and OSMR genes linked to regeneration and therapy resistance (Figure 4). PROX1-high metastatic cells show reduced expression levels of non-canonical gene signatures. Targeting PROX1 may offer promising avenues for developing novel treatments for CRC.

A database-wide investigation of CRC progressive plasticity using the Talk2Data platform reveals findings consistent with [2]. Moving forward, analyzing an expanded database of CRC research studies with a larger number of sequenced cells will enhance our understanding of CRC metastasis plasticity. This will support the development of advanced cancer therapies that target progressive plasticity.

References:

1. https://www.who.int/news-room/fact-sheets/detail/colorectal-cancer

2. Moorman, A., Benitez, E.K., Cambulli, F. et al. (2024) Progressive plasticity during colorectal cancer metastasis. Nature; doi:10.1038/s41586-024-08150-0.

3. Espinoza, I. and Agarwal, S. et al. (2021) Expression of trefoil factor 3 is decreased in colorectal cancer. Oncology Reports; doi:10.3892/or.2020.7829.