Between-tumor and within-tumor heterogeneity in invasive potential

Area of Science:

• Oncology
• Genetics
• Biotechnology

Background:

• Breast cancer mortality is primarily driven by metastasis, which is challenging to study due to its complex, multi-year progression and the small fraction of cells involved.
• Within-tumor heterogeneity contributes to therapy failure and is often missed in bulk tissue analyses.
• Studying metastasis requires innovative approaches to capture cellular heterogeneity and track invasive processes.

Purpose of the Study:

• To exploit tumor heterogeneity for identifying molecular mechanisms of metastasis.
• To develop and validate novel statistical methods for analyzing organoid data to study metastasis.
• To identify molecular correlates of breast cancer invasion using patient-derived organoids.

Main Methods:

• Utilized patient-derived tumor organoids to model within-tumor heterogeneity.
• Developed population genetics and variance components models for statistical testing of organoid data.
• Quantified invasion phenotype using spectral power of organoid boundaries.
• Applied association tests to identify molecular markers linked to invasion.

Main Results:

• Organoids serve as reliable biological replicates, exhibiting similar within- and between-tumor variation.
• New statistical methods significantly amplify test power, with extreme phenotype organoids offering efficiency and cost savings.
• Identified a strong association between cancer cell invasion and Keratin 14 protein expression.
• Achieved highly significant p-values (p = 2 × 10-45 for within-tumor, p < 10-6 for pooled tests) for the invasion-Keratin 14 association.

Conclusions:

• Organoid-based approaches combined with advanced statistical methods offer powerful tools for studying metastasis.
• Keratin 14 is a significant molecular correlate of breast cancer invasion, potentially serving as a therapeutic target.
• These findings pave the way for discovering new cancer targets and developing novel therapeutics for metastasis.