Genetic and microenvironmental evolution of colorectal liver metastases under chemotherapy
Drug resistance limits the efficacy of chemotherapy for colorectal cancer liver metastasis (CRLM). However, the evolution of CRLM during drug treatment remains poorly elucidated. Multi-omics and treatment response data from 115 samples of 49 patients with CRLM undergoing bevacizumab (BVZ)-based chemotherapy show little difference in genomic alterations in 92% of cases, while remarkable differences are observed at the transcriptomic level. By decoupling intrinsic and acquired resistance, we find that hepatocyte and myeloid cell infiltration contribute to 38.5% and 23.1% of acquired resistance, respectively. Importantly, SMAD4 mutations and chr20q copy-number gain are associated with intrinsic chemoresistance. Gene interference experiments suggest that SMAD4<sup>R361</sup><sup>H/C</sup> mutations confer BVZ and 5-fluorouracil (5-FU) resistance through STAT3 signaling. Notably, supplementing BVZ and 5-FU with the STAT3 inhibitor GB201 restores therapeutic efficacy in SMAD4<sup>R361</sup><sup>H/C</sup> cancer cells. Our study uncovers the evolutionary dynamics of CRLM and its microenvironment during treatment and offers strategies to overcome drug resistance.
Authors
- Dongqiang Zeng (ORCID: https://orcid.org/0000-0001-9724-8325)
- Na Huang (ORCID: https://orcid.org/0000-0001-7961-0677)
- Yingxi Yang (ORCID: https://orcid.org/0000-0001-5153-2769)
- Zongchao Mo (ORCID: https://orcid.org/0000-0002-4107-9662)
- Wangjun Liao (ORCID: https://orcid.org/0000-0002-1364-8442)
- Genjie Huang (ORCID: https://orcid.org/0009-0001-7777-910X)
- Yijin Guan (ORCID: https://orcid.org/0009-0000-5121-9246)
- Jianan Cai (ORCID: https://orcid.org/0009-0008-7618-2951)
- Qiong Huang (ORCID: https://orcid.org/0000-0002-0570-5961)
- Quanhua Mu (ORCID: https://orcid.org/0000-0002-6891-5616)
- Xiaoxiang Rong (ORCID: https://orcid.org/0000-0002-5058-2067)
- Jihong Tang (ORCID: https://orcid.org/0000-0002-5518-640X)
- Xiaomeng Zhang (ORCID: https://orcid.org/0000-0002-3794-6823)
- Zhaojun Wang (ORCID: https://orcid.org/0000-0003-2853-1850)
- Jiao Wang (ORCID: https://orcid.org/0000-0001-9875-5425)
- Zhenhua Wu (ORCID: https://orcid.org/0000-0003-4552-883X)
- Chunlin Wang (ORCID: https://orcid.org/0000-0002-3411-0617)
- Min Shi (ORCID: https://orcid.org/0000-0002-2130-181X)
- Yizhi Liu (ORCID: https://orcid.org/0000-0003-4108-9593)
- Jian Guo
- Haixia Shang (ORCID: https://orcid.org/0000-0001-8821-3585)
- Ji-Guang Wang (ORCID: https://orcid.org/0000-0002-1225-0256)
Institutions
- Hong Kong University of Science and Technology (HK)
- Nanfang Hospital (CN)
- Southern Medical University (CN)
- University of Hong Kong (HK)
- South China University of Technology (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101838
- Citations
- 11
- Primary Topic
- Colorectal Cancer Treatments and Studies
- Type
- article
- Field-Weighted Citation Impact
- 3.11
Funders
- Natural Science Foundation of Guangdong Province