Multidimensional decoding of colorectal cancer heterogeneity: Artificial intelligence-enabled precision exploration of single-cell and spatial transcriptomics

Figure 1 Overview of the integration of colorectal cancer heterogeneity with single-cell RNA sequencing and spatial transcriptomics. This schematic illustrates key drivers of cellular diversity within defective mismatch repair (dMMR) colorectal cancer (CRC) tumors. Epigenetic origin: Hypermethylation of the MLH1 gene promoter CpG island drives the transition from normal colonic epithelium to dMMR CRC. Cellular heterogeneity: Non-mutational epigenetic reprogramming enables both symmetric division (expanding the cancer cell pool) and asymmetric division, generating distinct subpopulations with divergent properties: Proliferation-related, chemotherapy tolerance-related, invasion-related. Key regulators in this process include ATF6 and FOXQ1. Activating invasion and metastasis: Invasion-prone subclusters exhibit metabolic reprogramming centered on glutamine/amino acid metabolism, generating α-ketoglutaric acid to fuel the tricarboxylic acid cycle. Activation of hypoxia-inducible factor 1-alpha and oxoglutarate dehydrogenase, ultimately promoting invasive and metastatic behavior. dMMR: Defective mismatch repair; CRC: Colorectal cancer; CCSC: Cancer stem cell-like cell; ASCT2: Alanine-serine-cysteine transporter 2; SN2: Sodium-coupled neutral amino acid transporter 2; GLS: Glutaminase; GLS2: Glutaminase 2; IL-4: Interleukin-4; Gln: Glutamine; Glu: Glucose; GLUD: Glutamate dehydrogenase; OGDH2: Oxoglutarate dehydrogenase; α-KG: Alpha-ketoglutarate; TCA cycle: Tricarboxylic acid cycle; HIF-1: Hypoxia-inducible factor 1-alpha.