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Peer-reviewedCC BYCell

Uncovering spatially resolved functional genomics with CRISPR screen sequencing

  • Haorui Zhang1
  • Zongxu Zhang2
  • Peiyu Wang3
  • Tian Xu3
  • Xiaoyu Chen4
  • Yanping Zhao5,6
  • Siyu Lin1
  • Wenjie Cai1
  • Pengfei Ren3
  • Ce Luo1
  • Peng Zhang1
  • Yunfeng Wang3
9 more authors
  • Sen Hou7
  • Yahui Zhao5,6
  • Hu Zeng1
  • Zhihua Liu5
  • Cunyu Wang8
  • Zhidong Gao7
  • Yu Feng9
  • Deng Pan10
  • Zexian Zeng
10 affiliations
  1. 1Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China
  2. 2Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China
  3. 3Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China; Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China
  4. 4BGI Research, Hangzhou 310030, China
  5. 5State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing 100021, China
  6. 6Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
  7. 7Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100084, China
  8. 8Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, Peking University, Beijing 100871, China
  9. 9State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen 518083, China; BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan 030001, China. Electronic address: [email protected]
  10. 10School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: [email protected]
Open at sourceDOICite

Abstract

Spatial omics has advanced our understanding of tissue-level biology, yet tools to systematically link gene functional perturbations to spatial phenotypes and signaling pathways remain limited. To address this, we developed spatial CRISPR screen sequencing (SPAC-seq), a high-throughput spatial CRISPR screen platform, and TARDIS (target prioritization toolkit for perturbation data in spatial omics), a statistical spatial perturbation analysis toolkit. Using SPAC-seq and TARDIS, we linked gene perturbations to spatial phenotypes and pathways, uncovering how Icam1 loss in tumor cells promotes metastasis via immune suppression and macrophage polarization. In CD8 + T cells, we revealed Cd44 's role in regulating spatial phenotypes by interacting with Spp1 on macrophages. We also demonstrated the model of the transcription factor-chemokine receptor axis coupling cell states with chemotaxis. SPAC-seq and TARDIS provide an effective framework to study spatially resolved functional genomics and pathways across diverse biological and disease contexts.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026uncovering,
  title = {{Uncovering spatially resolved functional genomics with CRISPR screen sequencing}},
  author = {Haorui Zhang and Zongxu Zhang and Peiyu Wang and Tian Xu and Xiaoyu Chen and Yanping Zhao and Siyu Lin and Wenjie Cai and Pengfei Ren and Ce Luo and Peng Zhang and Yunfeng Wang and Sen Hou and Yahui Zhao and Hu Zeng and Zhihua Liu and Cunyu Wang and Zhidong Gao and Yu Feng and Deng Pan and Zexian Zeng},
  journal = {Cell},
  year = {2026},
  month = may,
  doi = {10.1016/j.cell.2026.04.049},
  url = {https://doi.org/10.1016/j.cell.2026.04.049},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Uncovering spatially resolved functional genomics with CRISPR screen sequencing
AU  - Haorui Zhang
AU  - Zongxu Zhang
AU  - Peiyu Wang
AU  - Tian Xu
AU  - Xiaoyu Chen
AU  - Yanping Zhao
AU  - Siyu Lin
AU  - Wenjie Cai
AU  - Pengfei Ren
AU  - Ce Luo
AU  - Peng Zhang
AU  - Yunfeng Wang
AU  - Sen Hou
AU  - Yahui Zhao
AU  - Hu Zeng
AU  - Zhihua Liu
AU  - Cunyu Wang
AU  - Zhidong Gao
AU  - Yu Feng
AU  - Deng Pan
AU  - Zexian Zeng
PY  - 2026
DA  - 2026/05/26
JO  - Cell
DO  - 10.1016/j.cell.2026.04.049
UR  - https://doi.org/10.1016/j.cell.2026.04.049
AB  - Spatial omics has advanced our understanding of tissue-level biology, yet tools to systematically link gene functional perturbations to spatial phenotypes and signaling pathways remain limited. To address this, we developed spatial CRISPR screen sequencing (SPAC-seq), a high-throughput spatial CRISPR screen platform, and TARDIS (target prioritization toolkit for perturbation data in spatial omics), a statistical spatial perturbation analysis toolkit. Using SPAC-seq and TARDIS, we linked gene perturbations to spatial phenotypes and pathways, uncovering how Icam1 loss in tumor cells promotes metastasis via immune suppression and macrophage polarization. In CD8 + T cells, we revealed Cd44 's role in regulating spatial phenotypes by interacting with Spp1 on macrophages. We also demonstrated the model of the transcription factor-chemokine receptor axis coupling cell states with chemotaxis. SPAC-seq and TARDIS provide an effective framework to study spatially resolved functional genomics and pathways across diverse biological and disease contexts.
SN  - 0092-8674
SN  - 1097-4172
ER  -