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Application of molecular activity probes to intravital imaging, however, often poses technical difficulties. Here, we sought to visualize extracellular signal-regulated kinase (ERK) activity in an orthotopic xenograft model of pancreatic cancer. Our custom-made pancreatic imaging window enabled long-term tracking (&amp;gt;2\u2005weeks) of cancer xenografts showing heterogeneous growth potential. Our validation approach of F\u00f6rster resonance energy transfer (FRET) imaging using a kinase-dead mutant ERK biosensor suggested that the local pH affects the ratiometric interpretation of FRET efficiency. Nevertheless, our FRET analysis allowed us to detect pharmacological inhibition of ERK activity, which supports the validity of the experimental model to dissect heterogeneous drug responses of cancer cells in their microenvironment. Of note, we found that the collagen signal was negatively correlated with local ERK activity heterogeneity, highlighting the benefit of our imaging system to observe the intricate pharmacodynamics modified by fibrosis. Our intravital live-imaging platform paves the way for a novel preclinical model that links molecular dynamics to the living tissue environment of pancreatic cancer.<\/jats:p>","DOI":"10.1242\/jcs.265075","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T10:53:15Z","timestamp":1791543195000},"source":"Crossref","is-referenced-by-count":1,"title":["FRET imaging of ERK activity in an orthotopic xenograft model of patient-derived pancreatic ductal adenocarcinoma using imaging window"],"prefix":"10.1242","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9205-5564","authenticated-orcid":false,"given":"Houssam","family":"Al-Koussa","sequence":"first","affiliation":[{"name":"Graduate School of Biostudies, Kyoto University 1 Laboratory of Cell Cycle Regulation , , Kyoto 606-8501 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