Quantitative Longitudinal Imaging Reveals that Inhibiting Hedgehog Activity Alleviates the Hypoxic Tumor Landscape

Area of Science:

• Oncology
• Molecular Biology
• Medical Imaging

Background:

• Metastasis is the primary cause of breast cancer mortality.
• Tumor hypoxia and dysregulated Hedgehog (Hh) signaling are linked to increased metastasis and poor prognosis.
• Hh signaling influences tumor cell behavior and the tumor microenvironment, promoting metastasis.

Purpose of the Study:

• To investigate the role of Hh signaling in establishing a hypoxic breast cancer environment.
• To explore the therapeutic potential of targeting Hh signaling in hypoxic breast cancer.
• To evaluate the use of hypoxia imaging for monitoring treatment response.

Main Methods:

• Utilized [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET) to image tumor hypoxia.
• Employed a syngeneic mammary tumor model with pharmacologic inhibition of Hh signaling.
• Analyzed Hh activity, HIF signaling, and VHL-dependent pathways in hypoxic conditions.

Main Results:

• Tumors with active Hh signaling exhibit a hypoxic microenvironment.
• Pharmacologic inhibition of Hh signaling reduces tumor hypoxia.
• Hh signaling is activated in hypoxic tumor cells, increasing HIF signaling in a VHL-dependent manner.

Conclusions:

• Hh signaling plays a critical role in creating a hypoxic tumor landscape and facilitating tumor cell adaptation to hypoxia.
• Targeting Hh signaling represents a potential therapeutic strategy for reducing breast cancer metastasis.
• Longitudinal hypoxia imaging can serve as a translational tool to assess the efficacy of Hh inhibitors like vismodegib in triple-negative breast cancer.