Collective cancer invasion forms an integrin-dependent radioresistant niche

Area of Science:

• Oncology
• Cancer Biology
• Cellular Signaling

Background:

• Metastatic dissemination and therapy resistance are key challenges in cancer treatment.
• These processes are influenced by signals within the tumor microenvironment.
• Understanding the interplay between invasion and resistance is crucial for developing effective therapies.

Purpose of the Study:

• To investigate how cancer cell invasion and therapy resistance cooperate.
• To identify molecular mechanisms driving invasion-associated radioresistance.
• To evaluate therapeutic strategies targeting integrins in combination with radiotherapy.

Main Methods:

• Intravital microscopy of orthotopic sarcoma and melanoma xenografts.
• Candidate-based approach to identify effectors of invasion-associated resistance.
• In vivo experiments combining radiotherapy with integrin monotargeting and dual targeting.

Main Results:

• Tumors invade collectively, with cells in the invasion zone exhibiting increased radioresistance and DNA damage repair.
• Targeting β1 or αV integrins individually with radiotherapy resulted in relapse and metastasis.
• Dual targeting of anti-β1 and anti-αV integrins with radiotherapy achieved relapse-free radiosensitization and prevented metastasis.

Conclusions:

• Invading cancer cells resist radiotherapy and DNA damage through β1/αV integrin cross-talk.
• Efficient radiosensitization requires targeting multiple integrins simultaneously.
• Combined anti-integrin therapy and radiotherapy offers a promising strategy to prevent cancer relapse and metastasis.