The David H. Koch Institute for Integrative Cancer Research at MITThe David H. Koch Institute for Integrative Cancer Research at MIT

Massachusetts Institute of Technology

National Cancer Institute Cancer Center

Science + Engineering... Conquering Cancer Together

Kristin Knouse, MD, PhD

Kristen Knouse. Credit: Gretchen Ertl, Whitehead Institute.

Assistant Professor of Biology

 

KI Research Areas of Focus:
MetastasisPersonalized Medicine

"We aim to understand how tissues sense and respond to damage with the goal of developing novel treatments for diverse human diseases. We focus on the mammalian liver, which has the unique ability to completely regenerate itself, in order to identify the molecular requirements for proliferative capacity and organ repair. To this end, we innovate genetic, molecular, and cellular tools that allow us to investigate and modulate organ injury and regeneration directly within living organisms. We will leverage our discoveries to identify novel therapeutic approaches for disease states ranging from tissue injury to cancer."

Kristin Knouse is an Assistant Professor in the MIT Department of Biology. She received a BS in biology from Duke University in 2010 and then enrolled in the Harvard and Massachusetts Institute of Technology (MIT) MD-PhD program, where she earned a PhD through the MIT Department of Biology in 2016 and an MD through the Harvard-MIT Division of Health Sciences and Technology in 2018. She conducted her doctoral research in the laboratory of Angelika Amon, where she developed tools to characterize large-scale somatic copy number alterations in mammalian tissues and then used diverse approaches to reveal the importance of tissue architecture for chromosome segregation fidelity in epithelia. In 2018, she established her independent laboratory as a Whitehead Fellow at the Whitehead Institute for Biomedical Research and was honored with the NIH Director’s Early Independence Award. In July 2021, she became an Assistant Professor in the MIT Department of Biology and Koch Institute for Integrative Cancer Research.

Research Summary

The damage or death of terminally differentiated cells in organs that lack active stem cell populations underlies the morbidity of numerous diseases including diabetes, heart attack, stroke, and neurodegeneration, as well as many aspects of aging. In these contexts, the differentiated cells permanently exit the cell cycle in the process of differentiation and therefore any remaining functional cells cannot replenish the lost cells. Undoubtedly, a means of enabling terminally differentiated cells to renew and proliferate could alleviate myriad diseases and counteract aging across organ systems.

Although proliferation and differentiation might seem mutually exclusive, the liver—and the hepatocytes responsible for the majority of its mass and function—stand out as notable and informative exceptions. In the uninjured liver, hepatocytes are quiescent and may remain in this non-proliferative state for months to years. However, if liver mass or function is ever compromised, these cells will immediately re-enter the cell cycle and proliferate to regenerate the organ. It is wholly unclear why hepatocytes can proliferate and the liver can regenerate but other differentiated cell types and organs cannot. We are innovating and employing tools to investigate and modulate organ injury and repair directly within living organisms. Our investigations will first and foremost fill critical gaps in our understanding of the quiescent state and liver regeneration and ultimately uncover new avenues for enabling regeneration across organ systems.

Beyond regenerative medicine, our studies of proliferative capacity across organs should provide a powerful new perspective on cancer. The most therapeutically intractable aspect of cancer is often not the rapidly proliferating cells that constitute primary tumors but rather the cells that disseminate from the primary tumor to sites throughout the body. These disseminated cancer cells can lie quiescent for years, evading the chemotherapies designed to target rapidly dividing cells, until ultimately re-entering the cell cycle and manifesting as metastatic disease. We will leverage our insights into quiescence and cell cycle re-entry to enable better understanding of dormant cancer cells. This knowledge will ultimately enable us to contribute to targeting disseminated cancer cells and preventing metastatic disease.

Selected Publications

Keys HR, Knouse KA. A genome-wide screen in the mouse liver reveals sex-specific and cell non-autonomous regulation of cell fitness. (In review)

Swartz SZ, McKay LS, Su KC, Bury L, Abbas P, Maddox PS, Knouse KA, Cheeseman IM. Quiescent cells actively replenish CENP-A nucleosomes to maintain centromere identity and proliferative potential. Developmental Cell. 2019. 51: 35-48.e7.

Knouse KA, Lopez KE. Bachofner M, Amon, A. Chromosome segregation fidelity in epithelia requires tissue architecture. Cell. 2018.175: 200-211.e213.

Stevens KR, Scull MA, Ramanan V, Fortin CL, Chaturvedi RR, Knouse KA, et al. In situ expansion of engineered human liver tissue. Science Translational Medicine 2017. 9: eaah5505.

Santaguida S, Richardson A, Iyer DR, M’Saad O, Zasadil L, Knouse KA, et al. Chromosome missegregation generates cell cycle-arrested cells with complex karyotypes that are eliminated by the immune system. Developmental Cell. 2017. 41: 638-651.

Knouse KA, Davoli T, Elledge SJ, Amon A. Aneuploidy in cancer: Seq-ing answers to old questions. Annual Review of Cancer Biology 2017. 1: 335-354.

Knouse KA, Wu J, Hendricks A. Detection of copy number alterations using single cell sequencing. Journal of Visualized Experiments. 2017. 120: e55143.

Pfau SJ, Silberman RE, Knouse KA, Amon A. Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo. Genes and Development. 2016. 30: 1395-1408.

Knouse KA, Wu J, Amon A. Assessment of megabase-scale somatic copy number variation using single cell sequencing. Genome Research. 2016. 26: 376-384.

Knouse KA, Wu J, Whittaker CA, Amon A. Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. PNAS. 2014. 111: 13409-13414.

Contact Information

Kristin Knouse

room 76-561
email knouse@mit.edu

Knouse Lab

website

Administrative Assistant:

Judy Teixeira
phone (617) 253-0263
email jteixeir@mit.edu