Single-cell spatial multiomics identifies POSTN+ CAFs mediating chemoradiotherapy resistance in rectal cancer
Sakai, S. A.; Okumura, M.; Morinaga, Y.; Kato, K.; Kojima, M.; Hofmann, F.; Reichholf, B.; Garcia, P. V.; Nakamura, Y.; Sakashita, S.; Nakamura, M.; Hojo, H.; Tsukada, Y.; Ito, M.; Shitara, K.; Bando, H.; Kojima, T.; Zenkoh, J.; Tatekawa, S.; Katsuki, S.; Ogawa, K.; Takahashi, Y.; Suzuki, A.; Suzuki, Y.; Tsuchihara, K.; Gremel, G.; Yamashita, R.; Kageyama, S.-I.
Show abstract
Neoadjuvant chemoradiotherapy (CRT) is standard for locally advanced rectal cancer (LARC), yet many patients retain residual disease. To resolve CRT-associated remodeling of the tumor microenvironment, we generated a multimodal spatial atlas from serial sections of paired pretreatment and post-treatment specimens from 24 patients using Xenium single-cell spatial transcriptomics and PhenoCycler multiplex proteomics, profiling 2.8 million cells; matched Visium HD datasets were generated on adjacent serial sections. Resistance was most strongly associated with fibroblast and myeloid programs adjacent to residual tumor. We identify a periostin (POSTN)-expressing CAF subset selectively enriched around residual tumor cells in non-responders, displaying a myofibroblastic phenotype and activating extracellular matrix remodeling, noncanonical WNT signaling, and immunosuppressive pathways. Tumor cells neighboring POSTN+ CAFs show consistent epithelial-mesenchymal transition signatures. Together, this atlas enables interrogation of CRT-induced spatial remodeling and nominates POSTN+ CAFs as key mediators and targets of CRT resistance, with direct relevance to CRT-based combination strategies.
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