Emerging Role of Extracellular Matrix Pathways as a Target in Pediatric Cancer Treatment

Recent research conducted at Children's Hospital Los Angeles has shed light on a crucial molecular difference between the two primary types of rhabdomyosarcoma, a common pediatric soft tissue cancer. This discovery paves the way for developing more tailored therapeutic strategies. The study, led by Dr. JinSeok Park, uncovering that rhabdomyosarcoma tumors harboring the PAX3-FOXO1 fusion gene exhibit significantly reduced interaction with the surrounding extracellular matrix (ECM), compared to tumors lacking this gene. When the fusion gene is deactivated experimentally, these tumor cells increase their interaction with the ECM, aligning more closely with the behavior of fusion-negative tumors. These insights highlight the ECM as a promising therapeutic target.

The research emphasizes the role of the tumor microenvironment in cancer progression. It was found that fusion-negative tumors rely heavily on TGFβ signaling to maintain their attachment to the ECM, which is vital for their survival. Disrupting this pathway causes tumor cell death. Conversely, fusion-positive tumors, due to the influence of the PAX3-FOXO1 gene, suppress TGFβ signaling, making these cancer cells less dependent on the ECM and more mobile, potentially facilitating metastasis.

Importantly, knocking out the PAX3-FOXO1 gene in fusion-positive cells increased their dependence on the ECM, rendering them vulnerable to similar treatment approaches used for fusion-negative tumors. This unified targeting strategy offers new hope for more effective therapies tailored to tumor genetics.

Rhabdomyosarcoma originates from skeletal muscle cells and exhibits two main molecular subtypes: those with the PAX3-FOXO1 fusion gene (fusion-positive), generally associated with aggressive behavior and poorer prognosis, and fusion-negative types. Current treatments—surgery, chemotherapy, and radiation—apply broadly to both, despite their molecular differences. The findings from Dr. Park's team aim to develop targeted therapies that consider these molecular distinctions, especially focusing on the tumor microenvironment.

Future research is focused on understanding how varying levels of PAX3-FOXO1 expression influence tumor behavior and treatment response. This approach hopes to enhance personalized treatment plans, ultimately improving outcomes for children affected by this disease.