The limited availability of appropriate disease models is a major bottleneck that limits research impact. If model systems representing the genetic diversity of diseases such as cancer were readily available, experiments to understand the biological consequence of particular gene mutations and to develop new therapeutic strategies could proceed more rapidly.
Until recently, despite enormous effort dedicated to the creation of cancer cell line models, success rates have been very low (often zero). However, exciting technology developments have recently changed the landscape of possibilities for systematic approaches to cell-line generation. These include protocols such as the Conditionally Reprogrammed Cells protocol developed by Richard Schlegel and colleagues at Georgetown University and the development of three dimensional organoid cultures by multiple groups including Hans Clevers at the Hubrecht Institute. Excitingly, many labs around the globe are starting to use these new methods.
There is great opportunity to come together to develop and deploy industrial strength SOPs to create models of every major cancer type at scale and make new models and methods broadly available. If hospitals and centers for cell line creation "factories" joined forces, the community could create large collections of genomically characterized disease models at scale and determine best practices to ensure open, unfettered access to the new models for the scientific community.
Excitingly, the Broad Institute is now part of the Human Cancer Models Initiative (HCMI), an international consortium that is generating novel human tumor-derived culture models, which are annotated with genomic and clinical data.
The mapping of cancer genomes is nearly complete. With this information in hand, the promise of developing and deploying customized cancer therapies that match the genetics of each particular patient's tumor has become the central goal for the translational cancer research community. While there is much that we can learn directly from cancer patients and their responses to therapeutics, a complementary approach of generating large-scale laboratory information is necessary to accelerate progress. We must actively manipulate cancer models (pieces of tumors that are propagated in the laboratory) to determine how the genes and mutations drive cancer vulnerabilities.
Over the last 50 years, the worldwide cancer research community has generated about 1000 cancer models. For decades, this seemed like a sufficiently large number to model many of the types of cancer that were known. But, now that we more fully understand the incredible genetic diversity of cancer it is clear that many thousands of new models are needed to ensure that faithful models of the mutations present in each cancer patient exist.
In addition, despite enormous effort dedicated to the creation of cancer cell line models, success rates for certain cancer types have been very low (often zero) and genetic factors promoting or restricting success are completely unclear. For instance, standard approaches nave netted almost zero successes in prostate cancer or neuroendocrine tumors. Even for cancer types in which many cell-line models exist (e.g. 150 lung cancer cell lines), many common mutations are poorly represented in existing cell lines and the complex genetic combinations found in individual patients are not present in any existing model.
An ecosystem of cancer cell line factories to support a cancer dependency map.
Boehm JS, Golub TR. Nat Rev Genet. 2015 Jun 16. doi: 10.1038/nrg3967
We have launched a pilot Cell Line Factory project at the Broad Institute, together with hospital partners, to explore how best to overcome current obstacles, produce faithful models at scale and explore the ethical issues associated with enabling rapid and unfettered access. Our pilot effort has 4 goals: