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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
Patient-Derived in Vitro Models Reveal Insights into Medullary Thyroid Cancer Microenvironment and Resistance to
Elisa Stellaria Grassi1, Viola Ghiandai1, Germano Gaudenzi2
1Department of Endocrine and Metabolic Diseases, Laboratory of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milano, Italy.
Background:
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy with a 10-year mortality rate up to 50%. Current therapies for metastatic MTC comprise various tyrosine-kinase inhibitors, but resistance often appears due to the need for lifelong treatments. Like in other tumors, genetic, epigenetic, post-transcriptional, post-translational, and cell-cell interaction events influence drug response. However, progress in understanding MTC biology is limited by the lack of reliable in vivo and in vitro models. This study aims to develop a patient-derived model faithfully reproducing the microenvironmental alterations present in MTC.
Methods:
We applied a two-step protocol consisting of a first phase in which primary cells are cultivated as multicellular spheroids and a second phase in which they are switched to adherent cultures. After evaluation of the genetic background by targeted Next Generation Sequencing, we characterized our cells phenotype by examining a panel of stem/progenitor-related markers, the secretory abilities by ELISAs, the drug response by proliferation assays, the in vivo angiogenic and invasiveness by the use of zebrafish model, the in vitro invasivity by Matrigel Dome assays and the spatial variation of stem/progenitor marker in both 3D cell models and tissue samples by confocal microscopy.
Results:
Our model allowed the establishment of eight MTC patient-derived cell lines with different genetic backgrounds. The cultures faithfully reproduced the changes in stem and progenitor markers that we detected in our cohort of MTC tissue samples and could be successfully xenotransplanted in zebrafish model, showing both angiogenetic and invasive properties. Drug screening assays revealed the potential of our model for the study of patient-specific responses, as we were able to identify different candidate regulators of the sensitivity to currently available therapies for MTC.
Conclusions:
Our two-step protocol successfully generated primary MTC lines that maintain high plasticity, can be cultivated for several passages, and recreate the heterogeneity observed in patients' tissues. Our model will offer a robust platform for preclinical drug testing and mechanistic studies, addressing a longstanding gap in MTC research. It enables exploration of tumor microenvironment interactions and personalized therapeutic responses, supporting progress beyond current genomic-driven frameworks.
Insights
Researchers developed a novel patient-derived model for medullary thyroid carcinoma (MTC) to study drug resistance. This model accurately reflects MTC heterogeneity, aiding personalized treatment strategies for this rare cancer.
Area of Science:
- Oncology
- Translational Medicine
- Cancer Biology
Background:
- Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor with high mortality and frequent drug resistance.
- Current treatments for metastatic MTC, including tyrosine-kinase inhibitors, face challenges due to acquired resistance.
- Limited availability of reliable in vivo and in vitro models hinders understanding of MTC biology and drug response.
Purpose of the Study:
- To develop a patient-derived cell model that faithfully replicates the microenvironmental characteristics of MTC.
- To establish a platform for studying MTC heterogeneity and patient-specific drug responses.
- To address the gap in reliable preclinical models for medullary thyroid carcinoma research.
Main Methods:
- A two-step protocol involving spheroid and adherent cultures of primary MTC cells.
- Genetic profiling via targeted Next Generation Sequencing.
- Phenotypic characterization including stem/progenitor markers, secretory abilities, drug response assays, and in vivo/in vitro invasiveness studies using zebrafish and Matrigel assays.
Main Results:
- Successfully established eight patient-derived MTC cell lines with diverse genetic backgrounds.
- The model recapitulated stem/progenitor marker changes observed in patient tissues and demonstrated angiogenic and invasive properties in vivo.
- Drug screening identified potential regulators of patient-specific sensitivity to existing MTC therapies.
Conclusions:
- The developed two-step protocol yields versatile MTC cell lines that maintain plasticity and heterogeneity, mirroring patient tumors.
- This robust model serves as a valuable platform for preclinical drug testing and mechanistic investigations in MTC.
- The model facilitates exploration of tumor microenvironment interactions and personalized therapeutic responses, advancing MTC research beyond genomic-based approaches.
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