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Updated: Dec 29, 2025
Orthotopic Implantation of Patient-Derived Cancer Cells in Mice Recapitulates Advanced Colorectal Cancer
Published on: February 10, 2023
Modeling rectal cancer to advance neoadjuvant precision therapy
Harinarayanan Janakiraman1,2, Yun Zhu1,2, Scott A Becker1,2
1Department of Surgery, Medical University of South Carolina, Charleston, SC.
Abstract:
Progress in rectal cancer therapy has been hindered by the lack of effective disease-specific preclinical models that account for the unique molecular profile and biology of rectal cancer. Thus, we developed complementary patient-derived xenograft (PDX) and subsequent in vitro tumor organoid (PDTO) platforms established from preneoadjuvant therapy rectal cancer specimens to advance personalized care for rectal cancer patients. Multiple endoscopic samples were obtained from 26 Stages 2 and 3 rectal cancer patients prior to receiving 5FU/RT and implanted subcutaneously into NSG mice to generate 15 subcutaneous PDXs. Second passaged xenografts demonstrated 100% correlation with the corresponding human cancer histology with maintained mutational profiles. Individual rectal cancer PDXs reproduced the 5FU/RT response observed in the corresponding human cancers. Similarly, rectal cancer PDTOs reproduced significant heterogeneity in cellular morphology and architecture. PDTO in vitro 5FU/RT treatment response replicated the clinical 5FU/RT neoadjuvant therapy pathologic response observed in the corresponding patient tumors (p < 0.05). The addition of cetuximab to the 5FU/RT regiment was significantly more sensitive in the rectal cancer PDX and PDTOs with wild-type KRAS compared to mutated KRAS (p < 0.05). Considering the close relationship between the patient's cancer and the corresponding PDX/PDTO, rectal cancer patient-derived research platforms represent powerful translational research resources as population-based tools for biomarker discovery and experimental therapy testing. In addition, our findings suggest that cetuximab may enhance RT effectiveness by improved patient selection based on mutational profile in addition to KRAS or by developing a protocol using PDTOs to identify sensitive patients.
Insights
New rectal cancer models (patient-derived xenografts and organoids) accurately mimic patient tumors and treatment responses, aiding personalized therapy and biomarker discovery for better rectal cancer outcomes.
Area of Science:
- Oncology
- Translational Research
- Cancer Biology
Background:
- Effective preclinical models are crucial for advancing rectal cancer therapy.
- Existing models often fail to capture the unique molecular and biological characteristics of rectal cancer.
- Lack of suitable models hinders personalized treatment strategies.
Purpose of the Study:
- To develop and validate patient-derived xenograft (PDX) and patient-derived tumor organoid (PDTO) platforms for rectal cancer.
- To assess the fidelity of these models in replicating human rectal cancer histology, mutational profiles, and treatment responses.
- To evaluate the potential of these platforms for personalized medicine, biomarker discovery, and experimental therapy testing.
Main Methods:
- Established subcutaneous PDX models from 26 Stage 2/3 rectal cancer patients' pre-neoadjuvant therapy samples.
- Developed PDTOs from rectal cancer specimens, preserving cellular heterogeneity.
- Validated PDX and PDTO models by comparing histology, mutational profiles, and 5-fluorouracil/radiation therapy (5FU/RT) response with patient clinical outcomes.
Main Results:
- 15 subcutaneous PDX models were generated, showing 100% histological correlation and maintained mutational profiles.
- PDX models accurately reproduced patient responses to 5FU/RT.
- PDTOs exhibited significant heterogeneity and replicated patient responses to 5FU/RT (p < 0.05).
- Cetuximab combined with 5FU/RT showed increased sensitivity in PDX/PDTOs with wild-type KRAS compared to mutated KRAS (p < 0.05).
Conclusions:
- Rectal cancer PDX and PDTO platforms serve as powerful translational research tools.
- These models facilitate biomarker discovery and experimental therapy testing for personalized rectal cancer care.
- Findings suggest cetuximab could enhance radiation therapy effectiveness, potentially guided by KRAS mutational status for patient selection.
