Single-cell mapping identifies MSI+ cells as a common origin for diverse subtypes of pancreatic cancer

Nirakar Rajbhandari; Michael Hamilton; Cynthia M Quintero; L Paige Ferguson; Raymond Fox; Christian M Schürch; Jun Wang; Mari Nakamura; Nikki K Lytle; Matthew McDermott; Emily Diaz; Hannah Pettit; Marcie Kritzik; Haiyong Han; Derek Cridebring; Kwun Wah Wen; Susan Tsai; Michael G Goggins; Andrew M Lowy; Robert J Wechsler-Reya; Daniel D Von Hoff; Aaron M Newman; Tannishtha Reya

doi:10.1016/j.ccell.2023.09.008

Single-cell mapping identifies MSI⁺ cells as a common origin for diverse subtypes of pancreatic cancer

Cancer Cell. 2023 Nov 13;41(11):1989-2005.e9. doi: 10.1016/j.ccell.2023.09.008. Epub 2023 Oct 5.

Authors

Nirakar Rajbhandari¹, Michael Hamilton¹, Cynthia M Quintero², L Paige Ferguson¹, Raymond Fox¹, Christian M Schürch³, Jun Wang⁴, Mari Nakamura², Nikki K Lytle¹, Matthew McDermott¹, Emily Diaz¹, Hannah Pettit², Marcie Kritzik⁵, Haiyong Han⁶, Derek Cridebring⁶, Kwun Wah Wen⁷, Susan Tsai⁸, Michael G Goggins⁹, Andrew M Lowy¹⁰, Robert J Wechsler-Reya¹¹, Daniel D Von Hoff⁶, Aaron M Newman¹², Tannishtha Reya¹³

Affiliations

¹ Departments of Pharmacology and Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA; Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA, USA.
² Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York City, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York City, NY, USA.
³ Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany.
⁴ Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
⁵ Departments of Pharmacology and Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA; Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA, USA; Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York City, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York City, NY, USA.
⁶ Molecular Medicine Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.
⁷ Department of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
⁸ Department of Surgery, The Medical College of Wisconsin, Milwaukee, WI, USA.
⁹ Departments of Pathology, Medicine and Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹⁰ Department of Surgery, Division of Surgical Oncology, University of California San Diego School of Medicine, La Jolla, CA, USA.
¹¹ Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York City, NY, USA; Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA; Department of Neurology, Columbia University Medical Center, New York City, NY, USA.
¹² Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹³ Departments of Pharmacology and Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA; Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA, USA; Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York City, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York City, NY, USA. Electronic address: t.reya@columbia.edu.

Abstract

Identifying the cells from which cancers arise is critical for understanding the molecular underpinnings of tumor evolution. To determine whether stem/progenitor cells can serve as cells of origin, we created a Msi2-Cre^ERT2 knock-in mouse. When crossed to CAG-LSL-Myc^T58A mice, Msi2-Cre^ERT2 mice developed multiple pancreatic cancer subtypes: ductal, acinar, adenosquamous, and rare anaplastic tumors. Combining single-cell genomics with computational analysis of developmental states and lineage trajectories, we demonstrate that MYC preferentially triggers transformation of the most immature MSI2⁺ pancreas cells into multi-lineage pre-cancer cells. These pre-cancer cells subsequently diverge to establish pancreatic cancer subtypes by activating distinct transcriptional programs and large-scale genomic changes, and enforced expression of specific signals like Ras can redirect subtype specification. This study shows that multiple pancreatic cancer subtypes can arise from a common pool of MSI2⁺ cells and provides a powerful model to understand and control the programs that shape divergent fates in pancreatic cancer.

Keywords: Musashi; Myc; acinar cell carcinoma; adenosquamous carcinoma; cancer; cell of origin stem cells; pancreatic cancer; single cell; tumor evolution.

Single-cell mapping identifies MSI⁺ cells as a common origin for diverse subtypes of pancreatic cancer

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