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Colorectal Cancer Patient-Derived 2D and 3D Models Efficiently Recapitulate Inter- and Intratumoral Heterogeneity.

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Summary

This study introduces novel 2D and 3D models from patient-derived colorectal cancer cells. These models effectively identify pre-existing drug resistance and tumorigenic clones within tumors, crucial for personalized oncology.

Keywords:
colorectal cancerorganoidspreclinical modeltumor heterogeneity

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Area of Science:

  • Oncology
  • Cancer Biology
  • Genomics

Background:

  • Pre-existing drug resistance and tumorigenicity in cancer cells contribute to therapeutic failure and tumor progression.
  • Current cancer models inadequately represent intratumor functional heterogeneity for personalized oncology.
  • Colorectal cancer (CRC) presents a significant challenge due to these factors.

Purpose of the Study:

  • To establish innovative 2D and 3D models using patient-derived cancer cells (PDCCs) and air-liquid interface (ALI) organotypic cultures from CRC.
  • To characterize these models for their ability to recapitulate tumor heterogeneity, genomic landscape, and drug response.
  • To identify and study pre-existing drug-resistant and highly tumorigenic clones within individual CRC tumors.

Main Methods:

  • Development of 2D and 3D models from patient-derived colorectal cancer cells (PDCCs).
  • Establishment of air-liquid interface (ALI) organotypic cultures from colorectal cancer (CRC) tumors.
  • Genomic and transcriptomic profiling of PDCCs and ALI cultures.
  • Single-cell-derived clone establishment and characterization.
  • Assessment of drug response (5-Fluoruracil) and tumorigenicity.

Main Results:

  • PDCCs demonstrated high efficiency, proliferation, stability, and recapitulated the genomic landscape of parental tumors.
  • ALI organotypic cultures retained the histological architecture of original tumors.
  • Both 2D and 3D models maintained transcriptomic profiles and showed similar 5-Fluoruracil response trends.
  • Pre-existing drug-resistant and highly tumorigenic clones were identified within individual CRC tumors.
  • Tumorigenic cancer cells did not consistently exhibit stem cell gene expression characteristics.

Conclusions:

  • The developed 2D/3D PDCC and ALI models provide a valuable platform for studying cancer cell heterogeneity.
  • These models facilitate the exploration of molecular mechanisms behind drug resistance and tumorigenicity in colorectal cancer.
  • The findings support the development of targeted therapies for drug-resistant or highly tumorigenic cancer cell populations.