Expansion of cell-to-cell communication drives the early development of pancreatic cancer, new research in mice finds

Discussions of cancer often stress the genetic mutations that drive disease by altering the normal function of cellular proteins. KRAS, for example, normally acts as an on/off switch for cellular proliferation, but mutations to the gene — common in lung cancer, colorectal cancer and pancreatic cancer — cause that switch to stay on.

Yet mutations are only half of the story.

Interactions between these genetic mutations and external factors, such as tissue injury that leads to inflammation, reshape both cells’ identities and their local environment in ways that foster cancer’s emergence and runaway growth.

In pancreatic cancer, these changes start to happen fast — within 24 to 48 hours after tissue damage. They happen predictably. And they greatly expand some cells’ ability to communicate and interact with nearby cells.

Those were the findings from a new study published May 11 in Science by an international research team led by investigators at Sloan Kettering Institute at Memorial Sloan Kettering Cancer Center (MSK) and IRB Barcelona. The research combined sophisticated genetically engineered mouse models and advanced computational methods to map the earliest cell states leading to pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer.

While the five-year survival rate for pancreatic cancer has been inching upward in recent years, it remains quite low — just 12%, according to the Pancreatic Cancer Action Network. The disease is usually not caught until the cancer is in advanced stages and, thanks in part to advances in treating other types of cancer, pancreatic cancer is the third-leading cause of cancer-related death.

The research aimed not only to shed light on the difficult-to-study early cellular events that give rise to pancreatic cancer, but also to find potential opportunities for medical intervention at earlier stages of the disease.

How Plasticity Drives Cancer

The ability for cells to shed their original identity and adapt is called plasticity. And this plasticity is enhanced by inflammation, the researchers found.

“These precancerous cells gain the ability to send and receive far more signals than a normal cell,” says computational biologist Dana Pe’er, PhD, one of the paper’s two senior authors. “And we saw that this isn’t random — it’s structured. You see the same patterns emerge over and over when you run the experiments in different mice.”

The study was led by co-first authors Cassandra Burdziak, a doctoral student in the Pe’er Lab, and Direna Alonso-Curbelo, PhD., a former member of the lab of co-senior author Scott Lowe, PhD, who now leads her own lab at IRB Barcelona.

In order to study the origins and impacts of plasticity on cells expressing a mutated version of KRAS, the scientists performed single-cell analyses on normal, inflamed, premalignant and malignant tissues using a genetically engineered mouse model designed to accurately recreate many aspects of pancreatic cancer in humans — from its earliest beginnings to metastasis.

“These models allowed us to capture the earliest changes in pancreatic epithelial cells as they progressed from a healthy state toward a malignant state,” says Dr. Lowe, a Howard Hughes Medical Institute Investigator and Chair of the Cancer Biology and Genetics Program at the Sloan Kettering Institute. The single-cell analyses allowed researchers to tease apart the characteristics of sub-populations of individual cells within the pancreas at each stage of progression and how their interactions further drive the progression.

“This project required a significant amount of computational innovation, most of it led by Cassandra,” notes Pe’er, who is also a Howard Hughes Medical Institute Investigator and who heads the Computational and Systems Biology Program at the Sloan Kettering Institute. “We had to invent a number of new methods to answer questions that aren’t typically asked about plasticity, cell-to-cell communication, and tumor progression.”

For example, the team invented a new classification score to measure the plasticity of a cell.

The team also found increased plasticity led to the enhancement of genes related to cell-to-cell communication: like those that encode ligands and receptors.

“Basically, these are genes that enable cells to send and receive signals from its environment and with other cells,” Pe’er says. “This gives the cell the ability to respond to signals that a normal cell wouldn’t be able to. They also have an enhanced ability to communicate with immune cells, and, as a result, the immune system around these cells starts to change.”

Additionally, the researchers were able to determine that a few sub-populations of cells, some of them quite rare, transform into major hubs of communication, driving a feedback loop that leads to the development and progression of pancreatic cancer.

The study represents the culmination of research initiated by Dr. Alonso-Curbelo, who has a long-standing interest in detailing the molecular mechanism by which inflammation promotes cancer initiation.

“This work was a true partnership between experimental science and computational science,” Dr. Alonso-Curbelo says.

Computational models were validated with follow-up experiments. “For example, imaging showed us that the populations of cells that computational methods said were talking to each other were significantly closer to each other in the tissue,” Burdziak says.

Through further experiments, the team was able to demonstrate that these conversations drive cancer development.

“We developed new mouse models to specifically block cell-to-cell signaling associated with neoplastic plasticity,” Dr. Alonso-Curbelo says. “These analyses showed that these expansive communication networks direct pancreatic tumor formation in the mice.“

Toward Clinical Applications

As a whole, the research provides a new, detailed understanding of how cells carrying a mutated copy of the KRAS gene gain plasticity and drive the progression of cancer when subjected to inflammation.

“This provides a roadmap that can help develop strategies to detect or possibly even prevent pancreatic tumors before they reach an incurable stage,” Dr. Lowe says. “And understanding how cell-to-cell communication networks drive the initiation of pancreatic cancer holds promise for the development of therapeutics to block or slow early cancer progression, and even potentially more advanced disease.”

Additional Authors, Funding, and Disclosures

Additional authors include: Francisco M. Barriga, Ronan Chaligné, Ojasvi Chaudhary, Hsuan-An Chen, Zi-Ning Choo, Yu-Jui Ho, Richard Koche, Wei Luan, Ignas Masilionis Tal Nawy, José Reyes, and Alexandra Wuest of MSK. Thomas Walle of MSK, the German Cancer Research Center, Heidelberg University Hospital, and the German Cancer Consortium. Doron Haviv, Vianne Gao, Yubin Xie, of MSK and the Tri-Institutional Training Program in Computational Biology and Medicine. Zhen Zhao of MSK and the Icahn School of Medicine. Chujun Julia Zhao of MSK and Columbia University. Linas Mazutis of MSK, Columbia University and Vilnius University. Daniela F. Quail and Yuhong Wei of McGill University.

This work was supported by Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center at MSK, the National Cancer Institute (P30 CA008748, F31CA24690, U54 CA209975), a La Caixa Junior Leader Fellowship (LCF/BQ/PI20/11760006), a FERO-ASEICA grant, the Spanish Cancer Research Association and Spanish Ministry of Science and Innovation (PID2021-128102OA-I00), an Edward P. Evans Young Investigator Award, a fellowship from the DKFZ Clinician Scientist Program, supported by the Dieter Morszeck Foundation, the Fraser Memorial Trust, a McGill MI4 Platform grant, Howard Hughes Medical Institute Fellowship of the Damon Runyon Cancer Research Foundation (DRG-2382-19), the National Institutes of Health (R25 CA233208), the Howard Hughes Medical Institute, Geoffrey Beene, the National Institute of Child Health and Human Development (HD084071), and the Starr Cancer Consortium.

MSK Disclosures: Dr. Lowe is a consultant and holds equity in Blueprint Medicines, ORIC Pharmaceuticals, Mirimus Inc., PMV Pharmaceuticals, Faeth Therapeutics, and Constellation Pharmaceuticals. Drs. Alonso-Curbelo and Lowe are listed as the inventors for a patent application covering methods for preventing or treating KRAS mutant pancreas cancer with inhibitors of type 2 cytokine signaling. Dr. Pe’er is on the scientific advisory board of Insitro. Dr. Walle T.W. reports stock ownership for Roche, Bayer, Innate Pharma, Illumina, and 10x Genomics, as well as research funding (not related to this study) from CanVirex AG, Basel Switzerland, and Institut für Klinische Krebsforschung GmbH, Frankfurt, Germany. Cassandra Burdziak, along with Drs. Alonso-Curbelo, Lowe and Pe’er are listed as inventors on a provisional patent application related to methods and compositions for treating PDAC, for which Memorial Sloan Kettering Cancer Center is the applicant.