2. Academic Validation
  3. Targeting intratumor heterogeneity suppresses colorectal cancer chemoresistance and metastasis

Targeting intratumor heterogeneity suppresses colorectal cancer chemoresistance and metastasis

  • EMBO Rep. 2023 Jun 20;e56416. doi: 10.15252/embr.202256416.
Shanshan Chao # 1 2,  Fei Zhang # 1 2,  Huiwen Yan # 1,  Liuyang Wang 3,  Liwen Zhang 1 2,  Zhi Wang 1 2,  Ruixin Xue 1 2,  Lei Wang 4,  Zhenzhen Wu 1 2,  Bing Jiang 5,  Guizhi Shi 4 6,  Yuanchao Xue 1 2,  Junfeng Du 7 8 9,  Pengcheng Bu 1 2 10
Affiliations

Affiliations

  • 1 Key Laboratory of RNA Biology, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 2 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
  • 3 Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC, USA.
  • 4 Laboratory Animal Research Center, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 5 Nanozyme Medical Center, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
  • 6 Aviation General Hospital of Beijing, Medical University and Beijing Institute of Translational Medicine, University of Chinese Academy of Sciences, Beijing, China.
  • 7 Department of General Surgery, The 7th Medical Center, Chinese PLA General Hospital, Beijing, China.
  • 8 The 2nd School of Clinical Medicine, Southern Medical University, Guangdong, China.
  • 9 Medical Department of General Surgery, The 1st Medical Center, Chinese PLA General Hospital, Beijing, China.
  • 10 Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing, China.
  • # Contributed equally.
PMID: 37338390 DOI: 10.15252/embr.202256416
Abstract

Intratumor heterogeneity (ITH) is a barrier to effective therapy. However, it is largely unknown how ITH is established at the onset of tumor progression, such as in colorectal Cancer (CRC). Here, we integrate single-cell RNA-seq and functional validation to show that asymmetric division of CRC stem-like cells (CCSC) is critical for early ITH establishment. We find that CCSC-derived xenografts contain seven cell subtypes, including CCSCs, that dynamically change during CRC xenograft progression. Furthermore, three of the subtypes are generated by asymmetric division of CCSCs. They are functionally distinct and appear at the early stage of xenografts. In particular, we identify a chemoresistant and an invasive subtype, and investigate the regulators that control their generation. Finally, we show that targeting the regulators influences cell subtype composition and CRC progression. Our findings demonstrate that asymmetric division of CCSCs contributes to the early establishment of ITH. Targeting asymmetric division may alter ITH and benefit CRC therapy.

Keywords

asymmetric division; colorectal cancer; colorectal cancer stem-like cell; tumor heterogeneity.

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