Research Spotlight: ‘Cell Line Atlas’ Provides a Crucial Resource for Developing Therapies for Biliary Tract Cancer

Nabeel El-Bardeesy, PhD, the John R. Gallagher III and Katherine A. Gallagher Endowed Chair in Gastrointestinal Cancer Research at Massachusetts General Hospital and an associate member at the Broad Institute, is a co-senior author of a paper published in Cancer Discovery, “Generation of a biliary tract cancer cell line atlas identifies molecular subtypes and therapeutic targets.”

Gad Getz, PhD, a core institute member at the Broad Institute and the Paul Zamecnik, MD Endowed Chair in Oncology Basic Research at the Mass General Cancer Center, is a co-senior author; Francisca Vazquez, PhD, director of the Cancer Dependency Map Project (DepMap) at the Broad Institute, is a co-senior author; Vindhya Vijay, PhD, of the Krantz Family Center for Cancer Research at MGH, is a co-lead author; and Negin Karisani, PhD, of the Broad Institute and Krantz Family Center for Cancer Research is a co-lead author.

Q: How would you summarize your study for a lay audience?

Advanced biliary tract cancer (BTC) includes cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. BTC is a rare and aggressive group of cancers, carrying one of the worst prognoses in all of oncology. Only about 10% of patients survive beyond five years. Although these cancers differ significantly depending on where they arise within the biliary system—a network of ducts that transports bile to aid digestion—most patients receive the same standard treatment: a combination of chemotherapy and immunotherapy, which has limited effectiveness. Targeted therapies exist for a subset of patients with specific genetic alterations. But these treatments rarely result in lasting benefit, and many patients have no established treatment options once first-line therapy fails.

To improve treatment for all patients, a key challenge is understanding tumor diversity at the molecular and functional levels. To address this, we developed a “cell line atlas” which is a collection of cancer cell lines—each derived from an individual patient’s tumor and adapted to grow in the lab—with detailed characterization of their molecular features and vulnerabilities. This atlas serves as a resource to help better understand BTC biology and to guide the development of more effective, personalized treatment strategies.

Q: What motivated your study?

The field has long lacked a robust, well-characterized set of experimental models that reflect the genetic and biological diversity of BTC. This has been a major bottleneck in developing better treatments. Our aim was to build a resource that fills this gap: a large panel of patient-derived cell lines coupled with integrative analysis to uncover critical molecular pathways and potential therapeutic vulnerabilities. We specifically focused on enhancing the effectiveness of existing targeted therapies and on identifying novel treatment approaches, particularly for patient subgroups not currently served by mutation-based strategies.

Q: What methods or approach did you use?

We developed about 30 new cell lines, roughly doubling the number available to date, and performed deep analysis on each of the nearly 60 total cell line models using several approaches, including large-scale CRISPR screens as well as genomic and proteomic profiling. We then correlated these findings with data from human tumor specimens. To maximize impact, we integrated the entire dataset into DepMap, an open-access resource that spans more than 1,000 cancer cell lines, enabling comparisons across cancer types and broader accessibility for the research community.

Q: What did you find?

We identified new ways to classify BTC cell lines based on their molecular characteristics, essential gene dependencies, and drug sensitivity profiles. This revealed both shared and distinct biochemical pathways across BTC subtypes—some linked to specific genetic alterations, others defined by broader patterns of gene expression. In several contexts, we uncovered candidate therapeutic strategies associated with defined biomarkers. Importantly, many of the key features observed in the lab-based models were also evident in tumor samples from patients, underscoring their biological relevance.

Q: What are the implications?

Our findings provide important insights into previously unrecognized subtypes of BTC, each driven by distinct molecular programs. These insights offer a path toward more tailored, and potentially more effective, treatment strategies. In addition, the comprehensive datasets and cell line collection are publicly available, creating a foundational resource for other researchers in the field and supporting the development of better therapies to improve patient outcomes and quality of life.

Q: What are the next steps?

Our next steps include further characterizing the molecular subtypes identified in this study using additional patient samples and clinical data. We also plan to validate the most promising therapeutic strategies in preclinical models. This will help inform the design of clinical trials, especially in identifying opportunities to repurpose existing drugs, and in guiding the development of novel treatments for molecularly defined subgroups of BTC.

Authorship: In addition to Bardeesy, Vijay, Karisani, and Getz, Mass General Brigham authors include Lei Shi, Yu-Han Hung, Phuong Vu, Prabhat Kattel, Lauren Kenney, Joshua Merritt, Ramzi Adil, Qibiao Wu, Yuanli Zhen, Robert Morris, Johannes Kreuzer, Meena Kathiresan, Xcanda Ixchel Herrera Lopez, Haley Ellis, Ilaria Gritti, Lilian Lecorgne, Ines Farag, William Shen, Hiroyuki Kato, Qin Xu, Eranga R. Balasooriya, Meng-Ju Wu, Jinkai Wan, Hiroshi Kondo, Michael S. Lawrence, Krushna C. Patra, Vanessa S. Silveira, Cyril H. Benes, Vikram Deshpande, Dejan Juric, Cristina R. Ferrone, and Wilhelm Haas. In addition to Vazquez, other authors include Alexandra Popa, Saireudee Chaturantabut, Srivatsan Raghavan, Matthew D. Hall, Samarjit Patnaik, Min Shen, Robin K. Kelley, James M. Cleary, David E. Root, and William R. Sellers.

Paper cited: Vindhya V, et al, “Generation of a biliary tract cancer cell line atlas identifies molecular subtypes and therapeutic targets” Cancer Discovery DOI: 10.1158/2159-8290.CD-24-1383

Funding: This work was supported by grants from the Dependency Map Consortium and TargetCancer Foundation (TargetCancer Foundation Cholangiocarcinoma Cell Line Project, to N.B.). Additional support to N.B. was provided by the National Institute of Health (P50CA127003 and 1R01CA280085-01), CDMRP DOD Peer Reviewed Cancer Research Program (CA160216 and CA210849), Cholangiocarcinoma C2T2 Precision Oncology Award, and Evan Schumacher Fund for Rare Cancer Research, and V Foundation Translational Research Award.