Cancer is an illness caused by an uncontrolled division of transformed cells, which can originate in almost  any organ of the body.  Cancer is not a single disease, even when it arises in the same site of the body. Tremendous variability exists in progression of disease and response to therapy among different persons with the same general type of cancer, such as breast cancer. Even at the level of a single person, cancer cells show tremendous heterogeneity within a single tumor and among a primary tumor and metastases. This heterogeneity causes drug resistance and fatal disease. The prevailing dogma is that heterogeneity among cancer cells arises randomly, generating greedy individual cancer cells that compete for growth factors and optimal environments. The rare “winners” in this competition survive and metastasize. However, tumors consistently maintain heterogeneous subpopulations of cancer cells, some of which appear less able to grow and spread. This observation prompted Gary and Kathy Luker, cancer cell biologists at the University of Michigan, to hypothesize that cancer cells may actually collaborate under some circumstances to cause disease and not just compete. The idea that single, heterogeneous cancer cells work collectively within a constrained range of variability to drive population-level outputs in tumor progression is a ground-breaking concept that may revolutionize how we approach cancer biology and therapy.

The team is using innovative approaches to extract and merge data streams from models that generate heterogeneous cell behaviors

...cancer cell biologists have teamed up with computational scientists and experts in artificial intelligence to focus the power of these fields on understanding and overcoming heterogeneity in cancer.

To understand causes of single-cell heterogeneity in cancer and conditions that motivate cancer cells to collaborate, an interdisciplinary team of scientists at UM formulated an entirely new conceptual approach to this challenging problem. The cancer cell biologists have teamed up with computational scientists and experts in artificial intelligence to focus the power of these fields on understanding and overcoming heterogeneity in cancer. Building on large, single-cell data sets unique to the team, they will combine inverse reinforcement learning, an artificial intelligence method typically applied to discover motivations for human behaviors, with computational models inferred on the basis of the physics and chemistry of cell signaling and migration. They have proposed an entirely new conceptual approach combining single cell data, physics-based modeling and artificial intelligence to single-cell heterogeneity and intercellular interactions. By discovering  testable molecular processes underlying “decision-making” by single cells and their “motivations” for acting competitively or collaboratively, this research blazes a new path to understand and treat cancer. Their high-risk, high-reward approach to understand how each cell in a population processes information and translates that to action driving cancer progression, has attracted an award of $1 million dollars by the Keck Foundation. 

The team includes Gary Luker (Radiology, Microbiology and Immunology; Biomedical Engineering), and Kathryn Luker (Radiology), who are leading the experimental studies of cell signaling and migration; Jennifer Linderman (Chemical Engineering; Biomedical Engineering); and Krishna Garikipati (Mechanical Engineering; Mathematics), who are leading the machine learning and modeling side of the project. Nikola Banovic (Electrical Engineering and Computer Science) and Xun Huan (Mechanical Engineering) are using artificial intelligence approaches to discover decision-making policies and rewards for cancer cells, working with the rest of the investigators to incorporate experimental data and physics/chemistry-based models into their approaches.

The W. M. Keck Foundation was established in 1954 in Los Angeles by William Myron Keck, founder of The Superior Oil Company. One of the nation’s largest philanthropic organizations, the W. M. Keck Foundation supports outstanding science, engineering and medical research. The Foundation also supports undergraduate education and maintains a program within Southern California to support arts and culture, education, health and community service projects. This project incorporates elements from all the W. M. Keck Foundation’s focus research areas to tackle cancer with a novel, physics-based modeling and AI-centered approach.  The idea for this project originated in the 2020 MICDE faculty workshop in AI for Physically based Bio-medicine Workshop. The workshop brought together an interdisciplinary group of faculty members to discuss ways to advance artificial intelligence and machine learning methods for biomedical problems. After seeding the idea, a subset of these researchers were awarded an MICDE catalyst grant and a MIDAS PODS grant. These funds were used to establish the proof of concept and to generate preliminary results. 

Computational science is becoming increasingly indispensable in many areas of biomedical science. While the current proposal focuses on cancer, this innovative computational framework represents a transformative leap with widespread applications in multiple other biomedical, physical, and social sciences. MICDE supports innovative and interdisciplinary projects aiming to advance the current paradigms.

Portraits of Kathryn Luker, Gary Luker, Krishna Garikipati, Jennifer Linderman, Nikola Banovic and Xun Huan

Project’s principal investigators (left to right): Kathryn Luker (Radiology), Gary Luker (Radiology, Microbiology and Immonology, and Biomedical Engineering), Krishna Garikipati (Mechanical Engineering, and Mathematics), Jennifer Linderman (Chemical Engineering, and Mathematics), Nikola Banovic (Electrical Engineering and Computer Science) and Xun Huan (Mechanical Engineering).