In a new study in Nature Genetics (doi.org/10.1038/s41588-025-0…), we show that primary PDAC cells transcriptionally mimic major cell types of the liver (hepatocyte) or lung (bronchoalveolar) before migrating to those sites (metastasis). We observed the same phenomenon in several other cancer types, such as CRC, prostate and breast. Specifically, it is a 10-year prospective cohort snRNAseq study of PDAC patients with initial metastatic recurrence in either liver or lung: 👉In malignant compartment: 1) patients with liver initial metastasis have worse prognosis. The same pattern was observed in several different cancer types profiled in MSK-MET cohort (a targeted genomic study of top 505 genes implicated in cancer). 2) primary PDAC cells transcriptionally mimic the parenchymal cells of the metastatic site (lung vs liver), leading to successful seeding and colonization. We observed the same pattern in the primary and metastatic lesions of several different cancer types profiled in MET500 (metastatic lesions) and METMAP500 (primary cell lines). In sum, we did not identify specific tumor genomic alternations or genes as sole drivers of PDAC metastatic organotropism. 3) we report two single-cell signatures for liver vs lung recurrence in primary PDAC (applicable to other cancer types). The signatures can also be used to score bulk RNAseq samples. 4) a preliminary deep learning model (github.com/morchalabi/PDAC_o…) has been trained on the primary TME of our patients that predicts liver vs non-liver recurrence for new patients (single-cell transcriptomic data). 👉In non-malignant compartment: . we identify a new shorter potential route to cancer directly from ADM subpopulation. We show this route is enriched with patients with lung initial metastasis, while the classical route from atypical ductal cells is enriched with those with liver initial metastasis. 👉In CAF compartment: · we identify a new CAF population, pCAF, enriched with axonogenesis/axon guidance programs. pCAF was the main source of CXCL12 in the CAF compartment which together with CXCR4 are implicated in invasive PDACs. Enrichment of axonogenesis/axon guidance in pCAFs implies its role in neoinnervation. 👉In immune compartment: 1) while patients with liver initial metastasis were enriched with protumorigenic lymphocytes, patients with lung initial metastasis were enriched with proinflammatory but mostly exhausted lymphocytes. 2) among detected inhibitory immune checkpoints, TIGIT is the dominant exhaustion marker. 🙏 Special thanks to Amit Dipak for excellent protocol optimizing and library prep, Joy Fan and Mingxuan Zhang from Elham Aziz lab Lab for running Echidna for this cohort, and Drs. Alex Raufi, Michael Kluger, John Chabot and Anil Rustgi for their valuable insights and comments. 👉This paper should be read with: nature.com/articles/s41588-0… nature.com/articles/s41586-0… my website: morchalabi.github.io/MoriPag… 👉Similar research articles: nature.com/articles/s43018-0… nature.com/articles/s41586-0… nature.com/articles/s41586-0… nature.com/articles/s43018-0… doi.org/10.1038/s41588-025-0…