Oncogenic Linear Collagen VI of Invasive Breast Cancer Is Induced by CCL5

Area of Science:

• Oncology
• Biomaterials Science
• Cell Biology

Background:

• The tumor microenvironment, particularly the extracellular matrix (ECM), plays a critical role in cancer progression.
• Aligned, linear collagen at the boundaries of triple-negative breast tumors is associated with increased cancer cell invasion.
• The precise mechanism by which this linear collagen is formed remains largely unknown.

Purpose of the Study:

• To investigate the cellular mechanisms responsible for the formation of linear collagen at the tumor boundary.
• To identify key molecular players involved in organizing the extracellular matrix in triple-negative breast cancer.
• To explore potential therapeutic strategies targeting matrix organization for cancer treatment.

Main Methods:

• Development of an in vitro co-culture model mimicking the tumor border using MDA-MB-231 cells, adipose-derived stem cells, and dermal fibroblasts.
• Decellularization of the co-culture to analyze the resulting extracellular matrix structure and composition.
• Assessment of cell invasion through the engineered matrix.
• Investigation of paracrine signaling, specifically the role of chemokines like CCL5, in matrix formation.
• Utilizing monoclonal antibodies against CCL5 to disrupt matrix organization.

Main Results:

• The in vitro model successfully generated a linear extracellular matrix rich in pro-oncogenic collagen type VI, promoting cell invasion.
• Fibroblasts were identified as the producers of linear collagen VI, stimulated by a paracrine co-culture signal from adipose-derived stem cells and MDA-MB-231 cells.
• This paracrine signaling was mediated by high secretion levels of the chemokine CCL5.
• Blocking CCL5 with a monoclonal antibody resulted in a disorganized matrix with significantly reduced collagen VI and abrogated pro-oncogenic behavior in reseeded cells.

Conclusions:

• A cellular mechanism for creating linear extracellular matrix (ECM) in vitro has been elucidated.
• The chemokine CCL5 plays a crucial role in orchestrating the formation of striated tumor collagen.
• Targeting the CCL5-mediated pathway presents a potential strategy for disrupting tumor matrix organization and inhibiting cancer cell invasion in vivo.