Gandhi, Minakshi, Kramer, Melissa, Habel, Jill, Wang, Zihua, Utama, Raditya, Russo, Suzanne, Naik, Payal, Kostroff, Karen, Spector, David L (June 2025) Characterization of a Living Biobank of Patient-Derived Invasive Lobular Carcinoma Organoids that Retain Tumor Heterogeneity in 3D Culture and Tumorigenicity In Vivo. In: San Antonio Breast Cancer Symposium 2024, 2024 Dec 10-13, San Antonio, TX.
Abstract
Breast cancer (BC) is one of the primary causes of cancer related deaths among women worldwide. According to Cancer Statistics, over 310,720 new breast cancer diagnoses are expected in the United States in 2024 with an estimate of over 42,250 expected BC related deaths. Invasive Lobular Carcinoma (ILC) accounts for the 2nd most frequently diagnosed histological subtype of BC, constituting 10%-15% of all reported cases. ILC is hormonally driven (estrogen and progesterone receptors) with a hallmark characteristic of ILC being lack of E-cadherin (CDH1) and with mutations in the CDH1 gene reported in over 90% of cases. Mutations in the CDH1 gene have also been associated with 39%–52% increased lifetime risk of developing breast cancer in women. Patient-derived organoid (PDO) models have been shown to offer significant advantages in terms of better recapitulating the tumor/microenvironment niche, however such models have not been available to study ILC. With a vision to develop 3D models to better understand ILC and develop specific therapeutic targets, here, we describe the establishment and comprehensive characterization of a diverse biobank of ILC PDOs. We have performed in-depth genomic, transcriptomic and histologic profiling of the established ILC PDOs and validated the models to be true representatives of ILC tumors. Comprehensive genomic profiling of ILC PDOs using a custom 143 cancer driver gene panel (targeted exome sequencing) identified ILC specific mutations in CDH1, PIK3CA, TBX3, RUNX, etc. in PDOs. Short Multiply Aggregated Sequence Homologies (SMASH) identified widely reported copy number gains and losses (gains on Chr1q and losses on Chr16q and Chr17p among others) in established ILC PDOs. Transcriptomic profiling performed on matched tumor-normal pairs revealed the upregulation of ESR1 signalling-related pathways known to drive ILC carcinogenesis. Multiplexed single-cell RNA sequencing revealed that the established PDOs retained their cellular complexity and heterogeneity even after multiple passages and contained hormone responsive, hormone secretory, basal, fibroblasts, and proliferating populations of cells representing major cell types in ILC tumors. Lastly, we also show that the established ILC PDOs when xenografted (either in mammary glands or intra-ductally) in NOD-SCID gamma mice retain their tumorigenicity in vivo and the single file growth pattern, a characteristic of invasiveness in ILC tumors. In summary, we have established a living biobank of ILC PDOs often with matched normals (adjacent and/or distal) that are representative of different subtypes of ILC (classic, pleomorphic, tubule-lobular, mixed, etc.). Overall, this study has optimized a pipeline for establishment, culturing and validation of ILC PDOs as robust models available for studying ILC biology with a focus on basic, translational, and personalized medicine.
| Item Type: | Conference or Workshop Item (Poster) |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > breast cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Koo Lab CSHL labs > McCombie lab CSHL labs > Spector lab CSHL labs > Wigler lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 13 June 2025 |
| Date Deposited: | 26 Aug 2025 12:38 |
| Last Modified: | 26 Aug 2025 12:38 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41948 |
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