Core 2: Stanford Breast Metastasis Center Organoid Core

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Abstract/Project Summary Breast cancer research is substantially hampered by lack of experimental models that efficiently reflect physiological disease necessary to provide a comprehensive understanding of metastatic disease. Conventional cell lines and PDX models have contributed greatly to our understanding of breast cancer biology, but are inefficiently derived, do not fully capture the heterogeneity across breast cancer subtypes and rarely mimic clinical observations. Advancements in 3D organoid models from our lab and others have shown that patient- derived organoids (PDOs) can be generated efficiently, retain histologic and genetic features of originating tumor, closely mimic patient drug response and are amendable to scale for genomic functional screens. Recently, the Kuo lab developed next generation PDOs by developing an Air-Liquid Interface (ALI) culture system that enables culture of tumor epithelium en bloc with endogenous immune stroma (Cell, 2018). The advent of ALI organoid culture provides critical experimental models for studying the tumor microenvironment. Here, the Organoid Core provides essential patient derived organoid models for identifying the evolutionary dynamics and microenvironmental determinants of metastatic breast cancer for Stanford Breast Metastasis Center investigators. Co-led by breast cancer genomics expert Dr. Christina Curtis and organoid pioneer Dr. Calvin Kuo, the Stanford Breast Metastasis Center Organoid Core is uniquely positioned and qualified to address the unmet needs highlighted in this RFA: Metastasis Research Network, by providing novel experimental models to study metastatic dissemination patterns, cellular microenvironment crosstalk, and drug response. Here, the organoid core will provide patient-derived breast cancer submerged organoids from primary and metastatic tissue to study targeted drug resistance and to define specific metastatic patterns of breast cancer sub-clones in Project 1, along with genomic functional screens using CRISPR/CAS9 and macrophage-mediated phagocytosis in Project 3. Novel human breast cancer ALI organoid models will be extensively characterized as compared to originating tissue in collaboration with Projects 1 and 2. Further, ALI culture conditions will be optimized for functional tumor-immune crosstalk studies with Project 3. Upon successful completion, novel organoid models will provide critical experimental tools for defining metastatic driver genes and identifying therapeutic targets to overcome drug resistance and immune evasion.