To develop new targeted treatments for cancer, scientists need tissue models that accurately represent the genetic and molecular traits of the cancer they’re studying.

An international team led by researchers at MIT’s Koch Institute, the Broad Institute, the Dana-Farber Cancer Institute, the National Cancer Institute, and numerous other partnering institutions has developed nearly 700 new cancer models, derived from patient tumours, which they hope will aid in drug development.

These cells, which represent 25 different types of cancer, are now available for cancer researchers around the world to use.

The project is described in a new paper appearing today in Nature, with contributors from more than two dozen institutions.

The models are the result of a 10-year initiative, funded by the National Cancer Institute, to expand the number of patient-derived tissue models available.

For most of these models, the researchers converted tumour cells into organoids — 3D cell cultures that can survive indefinitely and mimic the genetic and molecular features of the tumours that they originally came from.

This type of model could help researchers identify new drug targets and test potential new treatments for many more types of cancer.

“Since the sequencing of the human genome and the analysis of cancer genomes over the last 20 years, we have had many ideas about cancer targets, but we need experimental systems in the lab to validate those targets and launch drug discovery projects,” says Jesse Boehm, a research scientist at the Koch Institute and one of the senior authors of the study.

From tumours to organoids

The Human Cancer Models Initiative was launched in 2016, following the completion of the Cancer Genome Atlas, an effort to catalogue the genomic alterations responsible for cancer growth.

For the atlas project, researchers sequenced cancer cell samples from thousands of patients.

That work revealed that the diversity of tumour genetic profiles was not fully captured by the roughly 1,000 patient-derived cancer cell lines that existed at the time.

“We realised that a thousand wasn’t enough, that the international community needed to invest in many more thousands to represent all cancers, all genotypes, all ethnicities,” Boehm says.

“Most existing models come from European and Southeast Asian patients, and many rare cancers are missing.”

Funded by the National Cancer Institute and the United Kingdom’s Wellcome Trust, hundreds of scientists across dozens of institutions participated in obtaining patient samples and developing them into cell lines that could be used for research.

“It’s been an enormous initiative, and this Nature paper is the culmination of that 10-year swath of activity,” Boehm says.

More than 2,700 tumour samples were obtained from hospitals participating in the study, from patients who gave their permission for their cells to be used for research.

These samples were collected by hospitals in the United States, the United Kingdom, and the Netherlands.

“A resource of this scale depends on the kind of systematic effort that often happens behind the scenes,” says Mushriq Al-Jazrawe, scientific director of the High Throughput Sciences (HTS) platform at the Koch Institute and one of the lead authors of the study.

“I’m especially grateful to the technical and scientific teams across the participating institutes whose careful, expert work turns patient tumour samples into well-characterised models and data that researchers everywhere can use with confidence.”

Most of these samples came from commonly seen cancers such as lung, liver, and pancreatic, but they also included about 150 rare types including tumours of the gallbladder and the small intestine.

To convert these samples into cells that can survive indefinitely in the lab, the researchers developed techniques for culturing the cells in specialised growth media with a scaffold that helps them grow into a 3D structure.

Overall, the researchers were able to successfully convert about one-third of the patient samples that they received.

Most of these new models consist of organoids, which in some cases more closely mimic the structure of the tissue that the cells came from.

Traditional cancer cell lines, which were developed beginning in the 1950s, exist as single layers of cells grown in a lab dish, while organoids consist of three-dimensional balls of cells embedded in a gelatin-like structure.

Once the organoids and cell lines were established, which can take up to a year, the researchers analysed them to make sure that their genomic sequences, RNA expression, and epigenomic modifications closely matched those of the tumour cells that they were derived from.

Cancer vulnerabilities

All of the models developed as part of the HCMI were deposited at the American Type Culture Collection (ATCC), a nonprofit distributor of cell lines.

Each model also has extensive data from the patient whose cells were used to start the cell line, including mutations that the patient inherited from their parents (germline mutations), and information on the cancer treatments they received.

Using these models, scientists should be able to perform much larger scale screens that could aid in drug development efforts.

In another paper also appearing in Nature today, Broad Institute researchers reported that they were able to profile more than 300 of the new models using high-throughput genome-sequencing, RNA sequencing, and more than 100 with CRISPR loss-of-function screens.

This enabled them to identify vulnerabilities in each model that could be targeted with new drugs.

These findings have been added to a resource known as the Cancer Dependency Map (DepMap), which now includes information on more than 2,000 types of cancer.

In another Nature companion paper, researchers at the Sanger Institute led an effort to characterise an additional 256 organoids developed through the HCMI project.

Additionally, even though most aspects of the formal HCMI project are currently winding down, researchers hope to continue developing models derived from additional patient tumour samples, including more paediatric cancers and rare cancers.

“We now have about 2,000, but if we really want to represent all humans with cancer in our preclinical research, more work is needed. We have to invite patients to donate tissue to make research tools that the whole world can use,” Boehm says.

“I think this will hopefully be not the end, but the beginning.”

“A major opportunity now is to carry the lessons of HCMI forward, so we can generate as much insight as possible from these precious tissue donations,” says Al-Jazrawe, who is also a researcher in the Broad Institute’s Cancer Programme.

“Here at HTS, we are continuing the work by developing methods to study patient-derived samples and models reproducibly and at scale, and by providing a platform for close collaboration with clinical and research teams.”

Other senior authors of the HCMI paper are Mathew Garnett of the Wellcome Sanger Institute, David Tuveson of Cold Spring Harbour Laboratory, Andrea Califano of Columbia University Vagelos College of Physicians and Surgeons, Paul Spellman of the University of California at Los Angeles, Keith Ligon of Dana-Farber Cancer Institute, Daniela Gerhard of the NCI Centre for Cancer Genomics, and Louis Staudt of the NCI Centre for Cancer Research.

In addition to Al-Jazrawe, the paper’s lead authors are Dina El-Harouni of the Broad Institute and Dana Farber, Seongmin Choi of Memorial Sloan Kettering Cancer Centre, Merve Dede of the University of Texas MD Anderson Cancer Centre, Toshinori Hinoue of the Van Andel Institute, Sean Misek of the Broad Institute and Dana-Farber, Heeju Hoh of the Institute of Systems Biology and the Columbia University Vagelos College of Physicians and Surgeons, and Luca Zanella of the Columbia University Vagelos College of Physicians and Surgeons.

Source: Massachusetts Institute of Technology