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Role of cancer-associated fibroblasts in head and neck cancer invasion and local recurrence

English title Role of cancer-associated fibroblasts in head and neck cancer invasion and local recurrence
Applicant Tolstonog Genrich
Number 152875
Funding scheme Project funding (Div. I-III)
Research institution Service d'oto-rhino-laryngologie CHUV
Institution of higher education University of Lausanne - LA
Main discipline Otorhinolaryngology
Start/End 01.09.2014 - 28.02.2018
Approved amount 458'023.00
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All Disciplines (3)

Discipline
Otorhinolaryngology
Experimental Cancer Research
Molecular Biology

Keywords (4)

cancer-associated fibroblasts; Notch signaling; head and neck cancer; local recurrence

Lay Summary (French)

Lead
Le cancer de la sphère ORL est une maladie hétérogène et agressive qui se développe dans les voies aérodigestives supérieures. En dépit des progrès récents dans l’approche thérapeutique, la récidive locale et régionale chez les patients atteints d’un cancer de la sphère ORL reste un sérieux problème clinique, puisque qu’elle est responsable de la majorité des échecs thérapeutiques. Par conséquent, un des enjeux scientifiques est de comprendre les mécanismes responsables de la récidive locale et régionale, et de développer de nouvelles approches thérapeutiques afin de prévenir la récidive tumorale.
Lay summary

La diffusion des cellules tumorales vers le tissu sain entourant la tumeur constitue un des facteurs responsables de la récidive tumorale. De nouvelles évidences ont suggéré qu’une telle diffusion des cellules, aussi appelée invasion, est dépendante de l’interaction entre les cellules tumorales et les cellules avoisinant la tumeur, et de manière plus spécifique avec les fibroblastes associés à la tumeur (CAFs). Il a été démontré que l’accumulation des CAFs corrèle avec un pronostic non favorable dans divers cancer épithéliaux, tel que le cancer tête et cou. De ce fait, une meilleure connaissance de l’interaction entre les cellules tumorales et les CAFs est une condition préalable pour le développement de nouvelles stratégies anti-tumorales afin de cibler simultanément les cellules tumorales et les CAFs. Dans notre projet, nous allons étudier le rôle des molécules liées à la voie signalisation Notch ainsi que celui du récepteur à domaine discoïdine lors de l’interaction cellulaire entre les cellules tumorales et les CAFs, et examiner de manière plus spécifique leurs rôles dans le processus d’invasion cellulaire et de récidive tumorale après un traitement chirurgical. Nous espérons que ces résultats augmenteront les connaissances sur les mécanismes d’invasion dans les cancers tête et cou et permettront l’identification de nouvelles cibles thérapeutiques.

Direct link to Lay Summary Last update: 09.07.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
The transcription factor FOXM1 regulates the balance between proliferation and aberrant differentiation in head and neck squamous cell carcinoma
Roh Vincent, Hiou‐Feige Agnès, Misetic Vinko, Rivals Jean‐Paul, Sponarova Jana, Teh Muy‐Teck, Ferreira Lopes Silvia, Truan Zinnia, Mermod Maxime, Monnier Yan, Hess Jochen, Tolstonog Genrich V, Simon Christian (2019), The transcription factor FOXM1 regulates the balance between proliferation and aberrant differentiation in head and neck squamous cell carcinoma, in The Journal of Pathology, 250(1), 107-119.
Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant
Bordignon Pino, Bottoni Giulia, Xu Xiaoying, Popescu Alma S., Truan Zinnia, Guenova Emmanuella, Kofler Lukas, Jafari Paris, Ostano Paola, Röcken Martin, Neel Victor, Dotto G. Paolo (2019), Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant, in Cell Reports, 28(9), 2358-2372.e6.
Cellular Barcoding Identifies Clonal Substitution as a Hallmark of Local Recurrence in a Surgical Model of Head and Neck Squamous Cell Carcinoma
Roh Vincent, Abramowski Pierre, Hiou-Feige Agnès, Cornils Kerstin, Rivals Jean-Paul, Zougman Alexandre, Aranyossy Tim, Thielecke Lars, Truan Zinnia, Mermod Maxime, Monnier Yan, Prassolov Vladimir, Glauche Ingmar, Nowrouzi Ali, Abdollahi Amir, Fehse Boris, Simon Christian, Tolstonog Genrich V. (2018), Cellular Barcoding Identifies Clonal Substitution as a Hallmark of Local Recurrence in a Surgical Model of Head and Neck Squamous Cell Carcinoma, in Cell Reports, 25(8), 2208-2222.e7.
Mouse model of postsurgical primary tumor recurrence and regional lymph node metastasis progression in HPV-related head and neck cancerSurgical model of HPV-related head and neck cancer
Mermod Maxime, Hiou-Feige Agnès, Bovay Esther, Roh Vincent, Sponarova Jana, Bongiovanni Massimo, Vermeer Daniel W., Lee John H., Petrova Tatiana V., Rivals Jean-Paul, Monnier Yan, Tolstonog Genrich V., Simon Christian (2018), Mouse model of postsurgical primary tumor recurrence and regional lymph node metastasis progression in HPV-related head and neck cancerSurgical model of HPV-related head and neck cancer, in International Journal of Cancer, 142(12), 2518-2528.
Trends in Surgical Research in Head and Neck Cancer
Tolstonog Genrich, Simon Christian (2017), Trends in Surgical Research in Head and Neck Cancer, in Current treatment options in oncology, 18(6), 38.

Collaboration

Group / person Country
Types of collaboration
Prof. Boris Fehse / University Medical Center Hamburg-Eppendorf Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Alexandre Zougman, Leeds Institute of Cancer & Pathology Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Amir Abdollahi / Translational Radiation oncology, German Cancer Research Center Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Tatiana Petrova, Department of Biochemistry, UNIL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
6th Faculty & Staff Retreat of the Lausanne Cancer Research Community 2017 Individual talk Analysis of clonal dynamics in HNSCC tumors by cellular barcoding: seeking the recurrence-initiating cells 14.11.2017 Lausanne, Switzerland Roh Vincent; Tolstonog Genrich; Zinnia Truan; Jean-Paul Rivals;
6th Faculty & Staff Retreat of the Lausanne Cancer Research Community 2017 Poster Role of fibroblastic Discoidin Domain Receptor 2 in head and neck cancer invasion and local recurrence 14.11.2017 Lausanne, Switzerland Roh Vincent; Jean-Paul Rivals; Zinnia Truan; Tolstonog Genrich;
5th Faculty & Staff Retreat of the Lausanne Cancer Research Community 2016 Poster DNA barcoding reveals clonal sweep and dominance in post-surgical HNSCC recurrence 08.11.2016 Lausanne, Switzerland Roh Vincent; Tolstonog Genrich; Jean-Paul Rivals;
5th Faculty & Staff Retreat of the Lausanne Cancer Research Community 2016 Poster Neck surgical model of highly aggressive HPV-positive head and neck squamous cell carcinoma in immune-competent mice 08.11.2016 Lausanne, Switzerland Tolstonog Genrich; Jean-Paul Rivals;
4th Faculty & Staff Retreat of the Lausanne Cancer Research Community 2015 Talk given at a conference Study of recurrent HNSCC disease in orthotopic mouse tumor models 10.11.2015 Lausanne, Switzerland Roh Vincent; Zinnia Truan; Tolstonog Genrich; Jean-Paul Rivals;


Associated projects

Number Title Start Funding scheme
144267 Integrative analysis of molecular and cellular mechanisms underlying therapy failure and local recurrence of head and neck cancers after surgery 01.08.2013 Project funding (Div. I-III)

Abstract

Head and neck cancer (HNC) is one of the most commonly diagnosed cancers worldwide. Loco-regional control, particularly the control at the primary tumor site, is an important prognostic factor for survival and clinical evidence has emerged that such local control depends greatly on an invasive phenotype of the primary cancer. In the recent years it became clear that cancer-associated fibroblasts (CAFs) are intimately involved in HNC progression and that their density and localization predict the aggressiveness of the disease and potential failure in the loco-regional control. Hence, we hypothesized that invasion and thus local control of HNCs may be related to CAFs in the proximity of the HNCs. We plan to address the three following aims in this study: Firstly, based on a membrane-enriched proteomic analysis of CAFs and tumor cell lines, established from clinical samples, we plan to correlate selected CAF-associated proteins with clinico-pathological characteristics. Secondly, based on our initial findings of an expression of NOTCH2 and the receptor tyrosine kinase DDR2 on the CAFs, we aim to investigate the role of these two proteins in the tumor-supportive function of CAFs. Finally, we will use our recently established xenogeneic and syngeneic orthotopic mouse models that specifically reconstitute the biological behavior of human HNC and in vitro co-cultures of patient-derived CAFs with HNC cells to demonstrate an in vivo effect of the functional circuitries between CAFs and tumor cells on tumor recurrence after surgical resection. Altogether, we plan to explore if modulation of CAFs and their interaction with tumor cells will reduce cancer cell invasion and prevent post-surgical HNC recurrence.
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