Haeger, Anna and Alexander, Stephanie and Vullings, Manon and Kaiser, Fabian M. P. and Veelken, Cornelia and Flucke, Uta and Koehl, Gudrun E. and Hirschberg, Markus and Flentje, Michael and Hoffman, Robert M. and Geissler, Edward K. and Kissler, Stephan and Friedl, Peter (2020) Collective cancer invasion forms an integrin-dependent radioresistant niche. JOURNAL OF EXPERIMENTAL MEDICINE, 217 (1): e20181184. ISSN 0022-1007, 1540-9538
Full text not available from this repository. (Request a copy)Abstract
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, we used intravital microscopy of orthotopic sarcoma and melanoma xenografts. We 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, we targeted beta 1 and alpha V beta 3/beta 5 integrins, essential extracellular matrix receptors in mesenchymal tumors, which mediate cancer progression and resistance. Combining radiotherapy with beta 1 or alpha V 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-beta 1/alpha V integrin dual targeting achieved relapse-free radiosensitization and prevented metastatic escape. Collectively, invading cancer cells thus withstand radiotherapy and DNA damage by beta 1/alpha V beta 3/beta 5 integrin cross-talk, but efficient radiosensitization can be achieved by multiple integrin targeting.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CIRCULATING TUMOR-CELLS; MONOCLONAL-ANTIBODY; RADIATION-THERAPY; HUMAN-MELANOMA; IN-VITRO; DNA; RESISTANCE; GROWTH; RADIOTHERAPY; BETA-1-INTEGRIN; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 07 Apr 2021 08:33 |
| Last Modified: | 07 Apr 2021 08:33 |
| URI: | https://pred.uni-regensburg.de/id/eprint/45488 |
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