Chemotherapy treatment induces pro-invasive changes in liver ECM composition

Area of Science:

• Oncology
• Cancer Metastasis
• Liver Biology

Background:

• Metastasis causes 90% of cancer deaths, with liver metastasis indicating poor prognosis for breast cancer patients.
• Chemotherapy, a standard treatment, can cause liver damage and fibrosis, but its effect on the liver's extracellular matrix (ECM) is unknown.
• The liver ECM influences cancer cell behavior, impacting metastatic outgrowth.

Purpose of the Study:

• To investigate how chemotherapy affects the liver microenvironment and its extracellular matrix (ECM).
• To determine if chemotherapy-induced changes in the liver ECM promote breast cancer metastasis.

Main Methods:

• Utilized MMTV-PyMT mouse models of breast cancer metastasis.
• Analyzed liver ECM composition using proteomics after paclitaxel treatment.
• Assessed cancer cell invasion and proliferation in response to altered liver ECM.
• Investigated the role of Collagen V, α1β1 integrins, and MAPK signaling in chemotherapy-induced pro-metastatic effects.
• Tested the efficacy of obtustatin, an α1β1 integrin inhibitor, on cancer cell invasion.

Main Results:

• The liver ECM from chemotherapy-treated mice enhanced breast cancer cell invasion, but not proliferation.
• Paclitaxel treatment increased Collagen V abundance in the liver ECM.
• Collagen V promoted cancer cell invasion via α1β1 integrins and MAPK signaling.
• Chemotherapy treatment led to increased alignment of Collagen I, associated with enhanced invasion.
• Obtustatin treatment inhibited cancer cell invasion in decellularized ECM from treated livers.

Conclusions:

• Chemotherapy alters the liver's extracellular matrix composition.
• These ECM changes create a pro-metastatic niche in the liver, promoting cancer cell invasion.
• Targeting Collagen V-α1β1 integrin interactions may offer therapeutic strategies to inhibit liver metastasis.