Onkologie/Steinbichler

​Forschungsschwerpunkte

• Predicitve biomarkers
• Therapy resistance in head and neck cancer
• Epithelial-mesenchymale transition
• Tumor-stroma interaction
• Tumor microenvironment
• Extracellular vesicles
• Liquid biopsy
• Salvage surgery

Approximately one third of all head and neck cancer patients at the Department of Otorhinolaryngology, Medical University of Innsbruck, are treated with first-line radiochemotherapy, especially with cisplatin. One fourth of these patients does not completely respond to first-line therapy. Patients with failure to radiochemotherapy can often be only offered rescue surgery as curative approach, which is associated with a high complication rate and permanent functional impairment. Additionally, patients with progressive disease after first-line therapy frequently presented with distant metastasis, further limiting curative treatment options. These data highlight the relevance of predicitive markers for radiochemotherapy resistance in head and neck cancer and the necessitiy of identifying molecular mechanism of therapy resistance to further improve patient outcome.

This study group focuses on clinical aspects of therapy failure, like the outcomes of salvage surgery but also on preclinical models analysing therapy resistance especially in the context of tumor stroma interaction and epithelial mesenchymal transition (EMT) as one major cause of radiochemotherapy resistance in head and neck cancer. EMT can be mimicked in vitro by co-cultivation of epithelial head and neck cancer cells and tumor-associated fibroblasts. EMT induced cisplatin and radiotherapy resistance of the cancer cells by the induction of anti-apoptotic signalling and increased DNA repair capacities. Furthermore, it increased migrational properties of the cancer cells and led to the induction of a mesenchymal phenotype (EMT). EMT can be assessed in HNC tumor probes by cytokeratin/vimentin co-expression and loss of E-cadherin/β-catenin co-expression. Slug immunohistochemistry was demonstrated to be a convenient surrogate marker for EMT. Consequently, Slug was introduced into our clinical routine immunohistochemical staining of tissue biopsies. Slug-positive patients had a 3.3 times better chance of survival when treated with upfront surgery ± radiotherapy versus primary radiochemotherapy in a multivariable Cox model (p = 0.017). For HNSCC patients, Slug IHC represents a novel and feasible predictive biomarker to support upfront surgery. Additionally, primary radiochemotherapy showed inferior response rates (univariate odds ratio (OR) for treatment failure, 3.6; 95% CI, 1.7 to 7.9; p = 0.001) and inferior 5-year OS (univariate, p < 0.001) in Slug-positive patients. 

Future perspectives include the identification of mediators of therapy resistance in EMT. As our in vitro model of EMT consists of a cell-free conditioned medium we suggest that either soluble signalling-factors or extracellular vesicles might be responsible for the observed effects of co-culture conditioned media. Exosomes are membranous vesicles with a diameter ranging from 40 to 100 nm and are constitutively released by almost all cell types, and mediate cell-to-cell communication by transferring mRNAs, miRNAs, DNAs and proteins causing extrinsic therapy resistance. Especially cancer cells secret high levels of exosomes (32). They transfer therapy resistance by anti-apoptotic signalling, increased DNA-repair or delivering ABC transporters to drug sensitive cells. As functional mediators of tumor-stroma interaction and of EMT, exosomes also promote environment-mediated therapy resistance. Extracellular vesicles are currently isolated from co-culture conditioned medium and analysed in more detail for their protein content. They could also be isolated from the blood of head and neck cancer patients in the context of liquid biopsy in the future.

Publications

• Delayed Reconstruction after Major Head and Neck Cancer Resection: An Interdisciplinary Feasibility Study. Steinbichler TB, Rauchenwald T, Rajsic S, Fischer HT, Wolfram D, Runge A, Dejaco D, Prossliner H, Pierer G, Riechelmann H. Cancers. 2023 May 16;15(10):2777
• Single- versus two-stage reconstruction in patients with head and neck cancer: What are the benefits? Rauchenwald T, Steinbichler TB, Rajsic S, Wolfram D, Prossliner H, Riechelmann H, Pierer G.J Plast Reconstr Aesthet Surg. 2023 Jun;81:76-82
• EMT-related transcription factors and protein stabilization mechanisms involvement in cadherin switch of head and neck squamous cell carcinoma. Ingruber J, Dudás J, Savic D, Schweigl G, Steinbichler TB, Greier MDC, Santer M, Carollo S, Trajanoski Z, Riechelmann H.Exp Cell Res. 2022 May 1;414(1):113084
• KLF4, Slug and EMT in Head and Neck Squamous Cell Carcinoma. Ingruber J, Savic D, Steinbichler TB, Sprung S, Fleischer F, Glueckert R, Schweigl G, Skvortsova II, Riechelmann H, Dudás J.Cells. 2021 Mar 3;10(3):539
• The Epithelial-Mesenchymal Transcription Factor Slug Predicts Survival Benefit of Up-Front Surgery in Head and Neck Cancer. Riechelmann H, Steinbichler TB, Sprung S, Santer M, Runge A, Ganswindt U, Gamerith G, Dudas J.Cancers. 2021 Feb 12;13(4):772
• Slug Is A Surrogate Marker of Epithelial to Mesenchymal Transition (EMT) in Head and Neck Cancer.
• Steinbichler TB, Dudas J, Ingruber J, Glueckert R, Sprung S, Fleischer F, Cidlinsky N, Dejaco D, Kofler B, Giotakis AI, Skvortsova II, Riechelmann H.J Clin Med. 2020 Jun 30;9(7):2061
• Epithelial to Mesenchymal Transition: A Mechanism that Fuels Cancer Radio/Chemoresistance.
• Dudas J, Ladanyi A, Ingruber J, Steinbichler TB, Riechelmann H.Cells. 2020 Feb 12;9(2):428
• Surgical rescue for persistent head & neck cancer after first-line treatment, Steinbichler TB, Golm L, Dejaco D, Riedl D, Kofler B, Url C, Wolfram D, Riechelmann H. Eur Arch Otorhinolaryngol., 2020 May;277(5):1437-1448
• Pleiotropic Effects of Epithelial Mesenchymal Crosstalk on Head and Neck Cancer: EMT and beyond. Steinbichler TB, Savic D, Dejaco D, Romani A, Kofler B, Skvortsova II, Riechelmann H, Dudas J. Cancer Microenviron. 2019 Jul 11.
• Therapy resistance mediated by exosomes. Steinbichler TB, Dudás J, Skvortsov S, Riechelmann H, Skvortsova II. Mol Cancer. 2019 Mar 30;18(1):58.
• Therapy resistance mediated by cancer stem cells. Steinbichler TB, Dudás J, Skvortsov S, Ganswindt U, Riechelmann H, Skvortsova II. Semin Cancer Biol. 2018 Dec
• Persistent Head and Neck Cancer Following First-Line Treatment. Steinbichler TB, Lichtenecker M, Anegg M, Dejaco D, Kofler B, Schartinger VH, Kasseroler MT, Forthuber B, Posch A, Riechelmann H. Cancers. 2018 Nov 3;10(11). 
• Epithelial-mesenchymal crosstalk induces radioresistance in HNSCC cells. Steinbichler TB, Alshaimaa A, Maria MV, Daniel D, Herbert R, Jozsef D, Ira-Ida S. Oncotarget. 2017 Dec 14;9(3):3641-3652
• Separation of cell survival, growth, migration, and mesenchymal transdifferentiation effects of fibroblast secretome on tumor cells of head and neck squamous cell carcinoma.
Metzler VM, Pritz C, Riml A, Romani A, Tuertscher R, Steinbichler T, Dejaco D, Riechelmann H, Dudás J., Tumour Biol. 2017Nov;39(11):1010428317705507
• The role of exosomes in cancer metastasis. Steinbichler TB, Dudás J, Riechelmann H, Skvortsova II., Semin Cancer Biol. 2017 Jun;44:170-181.,
• Tumor-associated fibroblast-conditioned medium induces CDDP resistance in HNSCC cells, Steinbichler TB, Metzler V, Pritz C, Riechelmann H, Dudas J. Oncotarget. 2016 Jan 19;7(3):2508-18

Cooperation

• Ira-Ida Skvortsova, Prof.Dr.,
• Dragana Savic
• EXTRO LAB
• Department of Therapeutic Radiology and Oncology
• Medical University of Innsbruck 
• Herbert Linder, Prof., PhD, Bettina Sarg, PD; Dr. rer.nat.
• Biocenter, Division of Clinical Biochemistry
• Medical University of Innsbruck 
• European Organisation for. Research and Treatment of Cancer (EORTC)

Team

Steinbichler Teresa Beranadette, PD, Dr.

Dr. Jozsef Dudas, PD, PhD

Mag.rer.nat. Julia Ingruber, PhD

Santer Matthias, Dr.

Herbert Riechelmann (until 2022)