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Cancer patients

Breakthrough in Colon Cancer Research Reveals New Insights into Therapy Resistance

Strategic Insights

— 2 min read

Researchers at Southeast University Medical School have made significant discoveries in the understanding of colon cancer, particularly in relation to therapy resistance. According to a recent study, the formation of tumor-derived vessel-like networks, known as vasculogenic mimicry (VM), has been identified as a key mechanism contributing to this resistance. The study, which was funded by the Bethune Charitable Foundation and the National Natural Science Foundation of China, used bioinformatic analyses of publicly available datasets and validated the results in patient samples to identify follistatin-like 3 (FSTL3) as a critical factor in VM formation.

Key Takeaways:

  • Follistatin-like 3 (FSTL3) is a critical factor that is predominantly expressed in colon cancer-associated fibroblasts (CCAFs) and is strongly correlated with increased VM formation, intratumoral blood vessels, and poor prognosis.
  • Single-cell RNA sequencing of tumors from VM and non-VM patients revealed that hypoxia drives FSTL3 expression in CCAFs, leading to extracellular matrix remodeling and enhancing cancer cell endothelial-like plasticity.
  • Mechanistically, FSTL3 binds to transferrin receptor (TfR1), an iron-uptake receptor on cancer cells, thereby activating the TfR1/AKT/mTOR pathway and elevating VE-Cadherin to support endothelial-like transformation, VM, and metastatic progression.
  • FSTL3-targeting antibodies (aFSTL3) effectively inhibited VM and angiogenesis in both in vitro and in vivo models, while the combination of aFSTL3 with bevacizumab produced synergistic suppression of neovascular-like structures and distant metastases.
  • The study found that FSTL3 plays a pivotal role in facilitating VM through TfR1-mediated signaling and offers a new dual-target approach to overcome anti-angiogenic therapy resistance in colon cancer.
  • The research was conducted by Yini Zhu and colleagues at Southeast University Medical School, and was funded by the Bethune Charitable Foundation and the National Natural Science Foundation of China.
  • Additional authors for the research include Leqian Ying, Lu Zhang, Min Ji, Meidan Wang, Lei Dong, Zhengcheng Yun, Yanping Chen, Jingyi Zhou, Chunchun Huang, Shengwei Zhang, Xuhong Yang, Hui Yang, Guichun Huang, Shukui Qin, Jinbing Xie, and Lin Liu.

Statistics:

  • 157 patient samples were used in the study to validate the results.
  • Bioinformatic analyses of publicly available datasets were used to identify FSTL3 as a critical factor in VM formation.
  • Single-cell RNA sequencing of tumors from VM and non-VM patients revealed that hypoxia drives FSTL3 expression in CCAFs.
  • FSTL3 binds to transferrin receptor (TfR1) with a binding affinity of unknown measure.
  • The TfR1/AKT/mTOR pathway is activated by FSTL3 binding to TfR1.
  • VE-Cadherin is elevated by FSTL3 binding to TfR1 to support endothelial-like transformation, VM, and metastatic progression.
  • The combination of FSTL3-targeting antibodies (aFSTL3) with bevacizumab produced synergistic suppression of neovascular-like structures and distant metastases.

Sources:

  • Cancer Weekly. Research Conducted at Southeast University Medical School Has Provided New Information about Colon Cancer (Cancer-associated fibroblasts expressing FSTL3 promote vasculogenic mimicry formation and drive colon cancer malignancy). p 1387.
  • Cell Death & Disease. Cancer-associated fibroblasts expressing FSTL3 promote vasculogenic mimicry formation and drive colon cancer malignancy. 2025;16(1):706.

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