Transcriptomic plasticity is a hallmark of metastatic pancreatic cancer

Jimenez-Sanchez, A.; Persad, S.; Hayashi, A.; Umeda, S.; Sharma, R.; Xie, Y.; Mehta, A.; Park, W.; Masilionis, I.; Chu, T.; Zhu, F.; Hong, J.; Chaligne, R.; O'Reilly, E. M.; Mazutis, L.; Nawy, T.; Pe'er, I.; Iacobuzio-Donahue, C. A.; Pe'er, D.

doi:10.1101/2025.02.28.640922

bioRxiv · 10.1101/2025.02.28.640922

Transcriptomic plasticity is a hallmark of metastatic pancreatic cancer

Jimenez-Sanchez, A.·Persad, S.·Hayashi, A.·Umeda, S.·Sharma, R.·Xie, Y.·Mehta, A.·Park, W.·Masilionis, I.·Chu, T.·Zhu, F.·Hong, J.·Chaligne, R.·O'Reilly, E. M.·Mazutis, L.·Nawy, T.·Pe'er, I.·Iacobuzio-Donahue, C. A.·Pe'er, D.

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Abstract

Metastasis is the leading cause of cancer deaths; nonetheless, how tumor cells adapt to vastly different organ contexts is largely unknown. To investigate this question, we generated a transcriptomic atlas of primary tumor and diverse metastatic samples from a patient with pancreatic ductal adenocarcinoma who underwent rapid autopsy. Unsupervised archetype analysis identified both shared and site-specific gene programs, including lipid metabolism and gastrointestinal programs prevalent in peritoneum and stomach wall lesions, respectively. We developed a probabilistic approach for inferring clonal phylogeny from single-cell and matched whole-exome data. Distantly related genetic clones in the peritoneum express the lipid metabolism program, likely due to signaling by the adipocyte-rich peritoneum environment, and cells in most clones express multiple programs, suggesting that transcriptomic plasticity is a prevalent feature of metastatic cells. These deeply annotated analyses using a patient-centric platform provide a model for investigating metastatic mechanisms and plasticity in advanced cancer.

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Jimenez-Sanchez, A., Persad, S., Hayashi, A., Umeda, S., Sharma, R., Xie, Y., Mehta, A., Park, W., Masilionis, I., Chu, T., Zhu, F., Hong, J., Chaligne, R., O'Reilly, E. M., Mazutis, L., Nawy, T., Pe'er, I., Iacobuzio-Donahue, C. A., Pe'er, D.. 2025-03-06. Transcriptomic plasticity is a hallmark of metastatic pancreatic cancer. https://doi.org/10.1101/2025.02.28.640922

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