Anna Häger and Peter Friedl, theme Cancer development and immune defense, and colleagues, identified a new niche of cancer cell survival and developed an integrin inhibition therapy to overcome resistance. They have published their results in the Journal of Experimental Medicine.
Cancer fatalities result from metastatic dissemination and therapy resistance, both processes that depend on signals from the tumor microenvironment. To identify how invasion and resistance programs cooperate, they used intravital microscopy of orthotopic sarcoma and melanoma xenografts. They demonstrate that these tumors invade collectively and that, specifically, cells within the invasion zone acquire increased resistance to radiotherapy, rapidly normalize DNA damage, and preferentially survive. Using a candidate-based approach to identify effectors of invasion-associated resistance, they targeted β1 and αVβ3/β5 integrins, essential extracellular matrix receptors in mesenchymal tumors, which mediate cancer progression and resistance. Combining radiotherapy with β1 or αV integrin monotargeting in invading tumors led to relapse and metastasis in 40–60% of the cohort, in line with recently failed clinical trials individually targeting integrins. However, when combined, anti-β1/αV integrin dual targeting achieved relapse-free radiosensitization and prevented metastatic escape. Collectively, invading cancer cells thus withstand radiotherapy and DNA damage by β1/αVβ3/β5 integrin cross-talk, but efficient radiosensitization can be achieved by multiple integrin targeting.
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