Spatial mapping of transcriptomic plasticity in metastatic pancreatic cancer

Guangsheng Pei, Jimin Min, Kimal I. Rajapakshe, Vittorio Branchi, Yunhe Liu, Benson Chellakkan Selvanesan, Fredrik Thege, Dorsay Sadeghian, Daiwei Zhang, Kyung Serk Cho, Yanshuo Chu, Enyu Dai, Guangchun Han, Mingyao Li, Cassian Yee, Kazuki Takahashi, Bharti Garg, Herve Tiriac, Vincent Bernard, Alexander Semaan, Jean L. Grem, Thomas C. Caffrey, Jared K. Burks, Andrew M. Lowy, Andrew J. Aguirre, Paul M. Grandgenett, Michael A. Hollingsworth, Paola A. Guerrero, Linghua Wang () and Anirban Maitra ()
Additional contact information
Guangsheng Pei: University of Texas MD Anderson Cancer Center
Jimin Min: University of Texas MD Anderson Cancer Center
Kimal I. Rajapakshe: University of Texas MD Anderson Cancer Center
Vittorio Branchi: University of Texas MD Anderson Cancer Center
Yunhe Liu: University of Texas MD Anderson Cancer Center
Benson Chellakkan Selvanesan: University of Texas MD Anderson Cancer Center
Fredrik Thege: University of Texas MD Anderson Cancer Center
Dorsay Sadeghian: University of Texas MD Anderson Cancer Center
Daiwei Zhang: University of Pennsylvania
Kyung Serk Cho: University of Texas MD Anderson Cancer Center
Yanshuo Chu: University of Texas MD Anderson Cancer Center
Enyu Dai: University of Texas MD Anderson Cancer Center
Guangchun Han: University of Texas MD Anderson Cancer Center
Mingyao Li: University of Pennsylvania
Cassian Yee: University of Texas MD Anderson Cancer Center
Kazuki Takahashi: Dana-Farber Cancer Institute
Bharti Garg: University of California, San Diego
Herve Tiriac: University of California, San Diego
Vincent Bernard: University of Texas MD Anderson Cancer Center
Alexander Semaan: University of Bonn
Jean L. Grem: University of Nebraska Medical Center
Thomas C. Caffrey: University of Nebraska Medical Center
Jared K. Burks: University of Texas MD Anderson Cancer Center
Andrew M. Lowy: University of California, San Diego
Andrew J. Aguirre: Dana-Farber Cancer Institute
Paul M. Grandgenett: University of Nebraska Medical Center
Michael A. Hollingsworth: University of Nebraska Medical Center
Paola A. Guerrero: University of Texas MD Anderson Cancer Center
Linghua Wang: University of Texas MD Anderson Cancer Center
Anirban Maitra: University of Texas MD Anderson Cancer Center

Nature, 2025, vol. 642, issue 8066, 212-221

Abstract: Abstract Patients with treatment-refractory pancreatic cancer often succumb to systemic metastases1–3; however, the transcriptomic heterogeneity that underlies therapeutic recalcitrance remains understudied, particularly in a spatial context. Here we construct high-resolution maps of lineage states, clonal architecture and the tumour microenvironment (TME) using spatially resolved transcriptomics from 55 samples of primary tumour and metastases (liver, lung and peritoneum) collected from rapid autopsies of 13 people. We observe discernible transcriptomic shifts in cancer-cell lineage states as tumours transition from primary sites to organ-specific metastases, with the most pronounced intra-patient distinctions between liver and lung. Phylogenetic trees constructed from inferred copy number variations in primary and metastatic loci in each patient highlight diverse patient-specific evolutionary trajectories and clonal dissemination. We show that multiple tumour lineage states co-exist in each tissue, including concurrent metastatic foci in the same organ. Agnostic to tissue site, lineage states correlate with distinct TME features, such as the spatial proximity of TGFB1-expressing myofibroblastic cancer-associated fibroblasts (myCAFs) to aggressive ‘basal-like’ cancer cells, but not to cells in the ‘classical’ or ‘intermediate’ states. These findings were validated through orthogonal and cross-species analyses using mouse tissues and patient-derived organoids. Notably, basal-like cancer cells aligned with myCAFs correlate with plasma-cell exclusion from the tumour milieu, and neighbouring cell analyses suggest that CXCR4–CXCL12 signalling is the underlying basis for observed immune exclusion. Collectively, our findings underscore the profound transcriptomic heterogeneity and microenvironmental dynamics that characterize treatment-refractory pancreatic cancer.

Date: 2025
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DOI: 10.1038/s41586-025-08927-x

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