Metastatic colorectal cancer (mCRC) remains a major clinical challenge due to heterogeneous treatment responses and the development of therapeutic resistance. Current tissue-based molecular profiling is limited by invasiveness and the inability to enable longitudinal monitoring. Extracellular vesicles (EVs) represent a promising source of non-invasive biomarkers, carrying stable RNA and proteins reflective of tumor biology. This study aims to identify and validate EV-derived transcriptomic and proteomic biomarkers to monitor disease evolution, predict treatment response, and support personalized management of patients with mCRC.
Age ≥ 18 years;
Histologically confirmed diagnosis of colorectal adenocarcinoma;
Radiological evidence of metastatic or locally advanced unresectable disease;
First-line treatment for metastatic disease already completed or ongoing according to standard clinical practice;
Absence of suitable biological samples or samples unsuitable for molecular analyses;
Incomplete clinical data preventing the performance of the planned analyses;
Insufficient quality of stored biological samples for the assessment of EV-RNA and EV-PROT analyses.
Age ≥ 18 years;
The retrospective cohort will include a total of 160 patients with metastatic colorectal cancer (mCRC) who have already received first-line systemic therapy (chemotherapy with or without biological agents), for whom biological samples and clinical data collected as part of routine clinical practice are available. Biological sample collection is planned for the period from 2017 to 2025. The prospective cohort will include 130 treatment-naïve patients with mCRC, who will be enrolled at the initiation of first-line therapy.
Cohort
Other
Blood sample
Other interventionCollection, in conjunction with blood sampling performed as part of routine clinical practice, of a 9 mL blood sample in an EDTA tube at the following time points: before treatment initiation, at the first radiological reassessment, and at disease progression. This sample collection is part of the standard clinical management of patients with metastatic colorectal cancer (mCRC).
Identification and Validation of Extracellular Vesicle-Derived Biomarkers in Metastatic Colorectal Cancer
The study aims to identify and validate circulating extracellular vesicle (EV)-derived biomarkers, including EV-RNA and EV-protein (EV-PROT) signatures, in patients with metastatic colorectal cancer (mCRC). The objective is to develop and validate an integrated, non-invasive biomarker panel to support patient stratification, predict response to systemic therapies, and enable longitudinal monitoring of disease evolution throughout treatment.
Identification of EV-RNA and EV-PROT Biomarkers in Metastatic Colorectal Cancer (Discovery Phase)
The discovery phase aims to identify novel EV-RNA and EV-PROT biomarkers derived from circulating extracellular vesicles in patients with metastatic colorectal cancer (mCRC). Biomarker candidates identified in plasma samples will be integrated with spatial transcriptomic and proteomic analyses of primary tumor tissues to assess their biological relevance. Functional validation will be performed using patient-derived colorectal cancer organoids (CRC-org), evaluating the effects of chemotherapy and targeted therapies on EV-derived biomarker expression.
Retrospective Validation of Biomarker Candidates in an Independent Cohort and Experimental Models
The identified EV-RNA and EV-PROT biomarkers will be retrospectively validated in an independent cohort of patients with metastatic colorectal cancer (mCRC). EV-RNA biomarkers will be assessed by droplet digital PCR (ddPCR), while EV-PROT biomarkers will be validated through nano-flow cytometry. Biomarker data will be integrated with clinical and pathological parameters to evaluate their association with treatment response, disease progression, and survival outcomes. Functional validation will be performed using patient-derived colorectal cancer stem cell models (CRC-org).
Prospective Validation and Assessment of the Clinical Utility of Biomarkers
The final phase will prospectively validate EV-RNA and EV-PROT biomarkers in an independent cohort of patients with metastatic colorectal cancer (mCRC) enrolled at two participating centers. Longitudinal plasma sample analyses collected at baseline, first radiological evaluation, and disease progression will assess the association between biomarker levels and clinical outcomes, including treatment response, progression-free survival (PFS), and overall survival (OS). Data from CRC-org models and 3D assembloids will be integrated with clinical and molecular findings to support the biological interpretation of the identified biomarkers and their potential role in therapeutic response and resistance mechanisms.
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