Related Experiment Video
Updated: Jul 12, 2026
Multiplex Immunofluorescence Combined with Spatial Image Analysis for the Clinical and Biological Assessment of the Tumor Microenvironment
Published on: June 2, 2023
Spatial multi-omics landscape of colorectal cancer macro- and micrometastases
Yang Liu1, Akshaya S Jadhav2, Yuwen Pan3
1Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Abstract:
Colorectal cancer (CRC) metastases frequently recur due to minimal residual disease (MRD) and persistent micrometastases after therapy. Here, we performed spatial multimodal profiling using spot-level and high-resolution spatial transcriptomics, multi-regional whole-genome sequencing following laser-capture microdissection, and high-plex protein imaging to map 49 tumors from 19 patients, encompassing paired primary CRC and matched liver (CLiM) and lung (CLuM) metastases. Phylogenetic reconstruction revealed that liver micrometastases (CLiMi) arose from early clonal divergences and harbored a stem-like, quiescent state consistent with metastatic dormancy. Spatially, we uncovered distinct stromal barriers: macrometastases were encapsulated by myofibroblasts, whereas micrometastases were surrounded by immunosuppressive niches characterized by T cell exhaustion and distinct ligand-receptor signaling networks. Notably, we identified a CLiMi-specific six-gene signature associated with MRD status, disease-free survival, and chemotherapy resistance across multiple independent cohorts. These findings elucidate the spatial evolutionary landscape of CRC metastases and provide tissue-based spatially validated biomarkers for surveillance and therapeutic targeting.
Insights
Colorectal cancer (CRC) micrometastases may cause recurrence by remaining dormant. This study maps CRC metastases, revealing distinct stromal barriers and identifying a gene signature linked to recurrence and treatment resistance.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Colorectal cancer (CRC) recurrence is often driven by minimal residual disease (MRD) and persistent micrometastases post-therapy.
- Understanding the spatial evolution and dormancy of these metastatic cells is crucial for improving patient outcomes.
Purpose of the Study:
- To spatially map colorectal cancer (CRC) primary tumors and matched liver (CLiM) and lung (CLuM) metastases.
- To investigate the evolutionary landscape, dormancy mechanisms, and microenvironment of CRC micrometastases.
- To identify novel biomarkers associated with MRD and treatment resistance.
Main Methods:
- Spatial multimodal profiling including transcriptomics and high-plex protein imaging.
- Multi-regional whole-genome sequencing with laser-capture microdissection.
- Phylogenetic reconstruction to analyze clonal evolution in paired primary CRC and metastases.
Main Results:
- Liver micrometastases (CLiMi) originate from early clonal divergences and exhibit a quiescent, stem-like state indicative of metastatic dormancy.
- Distinct stromal barriers differentiate macrometastases (myofibroblast encapsulation) from micrometastases (immunosuppressive niches with T cell exhaustion).
- A six-gene signature specific to CLiMi is identified, correlating with MRD status, disease-free survival, and chemotherapy resistance in independent cohorts.
Conclusions:
- Spatial evolutionary dynamics and microenvironmental interactions play a critical role in CRC metastasis and recurrence.
- The identified CLiMi-specific gene signature offers potential as a spatially validated biomarker for CRC surveillance.
- These findings support the development of targeted therapies to overcome dormancy and resistance in metastatic colorectal cancer.
