Probing Luminal Breast Cancer Treatment Response Heterogeneity with Zero-Passage Tumor Organoids 88 views

Luminal breast cancers (LBCs) are distinguished by expression of estrogen and progesterone hormone receptors (ER/PR) and comprise 70–80% of diagnosed breast cancers. Treatment consists of surgery, radiation therapy, and/or endocrine therapy. Many LBCs are or become resistant to standard-of-practice endocrine therapy, which motivates a deeper understanding of how luminal tumors differ. A major hurdle in studying LBC is the lack of adequate ways to maintain cells with primary luminal characteristics in culture. One promising new tool is 3D tumor organoids cultured directly from patient tumors. Organoids retain key phenotypic characteristics of each individual tumor and recapitulate some aspects of its architecture ex vivo. However, widespread use of luminal organoids is limited by the 20% success rate of long-term cultures and the loss of ER positivity over time, which makes it difficult to justify sacrificing primary tumor material and wastefully accruing patient consents on a large scale. To enhance the practicality of luminal organoids, we developed a streamlined protocol with collaborators in breast surgical oncology and anatomic pathology. The procedure eliminates the requirement for large tumor resections and instead begins with a few thousand cells scraped from the macrodissected surface of freshly removed tumor tissue. The method does not disrupt standard clinical procedures, the organoid success rate is ~50% after two weeks, and ER is maintained within the clinically relevant range. Importantly, pharmacologic, genetic, and radiotherapeutic manipulation of organoids yields quantifiable phenotypes within this time frame without any need for expansion and splitting. In this dissertation, we present the optimization and application of these “zero-passage” organoids as a platform for examining treatment response heterogeneity in LBCs. A future goal is to relate inter-patient variability of zero-passage organoids to long-term outcomes.

PHD (Doctor of Philosophy)

breast cancer; organoids; tumor heterogeneity

English

2026-04-25