Primary and metastatic cellular landscapes in human pancreatic cancer

Nina G Steele; Veerin R Sirihorachai; Ahmed M Elhossiny; Ian M Loveless; Padma Kadiyala; Monica Bonilla; Emily L Lasse-Opsahl; Carinna Solano Vargas; Katelyn L Donahue; Samantha B Kemp; Valerie Gunchick; Yatrik M Shah; Timothy L Frankel; Filip Bednar; Arvind Rao; Benjamin L Allen; Jiaqi Shi; Vaibhav Sahai; Howard C Crawford; Eileen S Carpenter; Marina Pasca di Magliano

doi:10.1016/j.isci.2025.113012

Primary and metastatic cellular landscapes in human pancreatic cancer

iScience. 2025 Jun 26;28(8):113012. doi: 10.1016/j.isci.2025.113012. eCollection 2025 Aug 15.

Authors

Nina G Steele^{1

2}, Veerin R Sirihorachai³, Ahmed M Elhossiny⁴, Ian M Loveless^{5

6}, Padma Kadiyala⁷, Monica Bonilla³, Emily L Lasse-Opsahl³, Carinna Solano Vargas⁸, Katelyn L Donahue³, Samantha B Kemp⁹, Valerie Gunchick^{10

11}, Yatrik M Shah^{10

12

13}, Timothy L Frankel^{11

13}, Filip Bednar^{11

13}, Arvind Rao^{4

13

14

15

16}, Benjamin L Allen^{1

13}, Jiaqi Shi^{13

17}, Vaibhav Sahai^{10

13}, Howard C Crawford², Eileen S Carpenter^{13

18}, Marina Pasca di Magliano^{1

11

13}

Affiliations

¹ Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
² Department of Surgery, Henry Ford Health Systems, Detroit, MI 48202, USA.
³ Cancer Biology Program, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Center for Bioinformatics, Department of Public Health Sciences, Henry Ford Health, Detroit, MI 48202, USA.
⁶ Department of Computational Mathematics, Science, and Engineering, Medical Imaging and Data Integration Lab, Michigan State University, East Lansing, MI 48824, USA.
⁷ Department of Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
⁸ College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA.
⁹ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁰ Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
¹¹ Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
¹² Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
¹³ Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁴ Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁵ Michigan Institute of Data Science (MIDAS), University of Michigan, Ann Arbor, MI 48109, USA.
¹⁶ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁷ Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁸ Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a complex tumor microenvironment (TME). We utilized single cell RNA sequencing to compare the TMEs of metastatic sites and primary tumors. We detected increased prevalence of exhausted CD8⁺ T cells in metastases, as well as the enrichment of complement pathway encoding genes in immunosuppressive tumor-associated macrophages, consistent with profound immunosuppression in metastatic disease. In cancer-associated fibroblasts, we identified a unique upregulation of metabolic genes, including UPP1, in metastasis. In cancer cells, we uncovered a specific gene signature upregulated in liver metastases; this signature was present in a proportion of primary tumors in the TCGA dataset, where it correlated with worse survival. Overall, our analysis of primary and metastatic PDAC defines a "high-risk" gene signature, metabolic reprogramming, and increased immune suppression in metastasis.

Keywords: Cancer; Integrative aspects of cell biology; Transcriptomics.

Abstract

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