Tissue homeostasis is highly regulated where the extracellular matrix plays multiple and essential roles. If this control is lost severe life threatening diseases can occur such as chronic inflammation, myocarditis, kidney failure and cancer. Understanding the molecular mechanisms of matrix actions will allow to fight cancer and other pathologies.
Tumors represent multi-cellular ecosystems where tumor, stromal and immune cells talk to each other and respond to their surrounding specific extracellular matrix that they produce. Here, integrins (recently awarded by the 2022 Lasker Award to Richard Hynes, Erkki Ruoslahti, and Timothy Springer (https://laskerfoundation.org/winners/integrins-mediators-of-cell-matrix-cell-adhesion/) are central players in generating the link of the cells to the extracellular matrix. The extracellular matrix of the tumor bed an important component of the so called tumor microenvironment does not only serve as architectual scaffold but also provides biochemical information that regulates cell behaviour and tumor immunity.
One of these matrix molecules that is highly expressed in cancer and shapes the tumor microenvironment is tenascin-C. Tenascin-C, an oncofetal molecule dicovered some 40 years ago by Ruth Chiquet-Ehrismann and others, plays multiple roles in tissue homeostasis, repair and diseases including cancer (Midwood et al., 2009, 2011, 2016, Yilmaz et al., 2022). Although tenascin-C is more famous for its roles in pathological contexts, tenascin-C acts as Danger Associated Molecular Pattern (DAMP) molecule in tissue repair and seems to have been coevolved with adaptive immunity (Orend & Tucker 2021). Tenascin-C executes diverse functions in a context dependent manner, however how is incompletely understood at the molecular level. Although mice with a knockout of tenascin-C are viable in the laboratory (which is likely not the case in the wild due to an aberrant behaviour), several abnormal phenotypes are observed upon injury. These mice thus were a useful tool to better understand tenascin-C actions in normal and pathological context. Upon tissue injury tenascin-C gets induced to elicit an acute immune response that is immediately turned off when the insult is gone and repair is finished. However, when tenascin-C expression remains high, as seen in chronic inflammation, cancer and fibrosis, tenascin-C excerbates the pathological phenotypes.
Our aim is to better understand the actions of tenascin-C in cancer to block the pathology promoting actions of tenascin-C while enhancing the anti-tumorigenic DAMP functions of tenascin-C. As tenascin-C is only marginally expressed at a few sites in healthy tissue, targeting tenascin-C may have little side effects. Thus several approaches are currently in development by several groups to target tenascin-C in cancer.
Research objectives of the laboratory:
- Establish murine models recapitulating human tumor matrix and immunity parameters
- Determine how tenascin-C regulates tumor immunity and events on the road to metastasis
- Develop prognostic parameters for cancer patient survival and selection of therapy
- Restore tumor immune surveillance by targeting tenascin-C
- Develop novel tenascin-C targeting tools
To better understand the roles of tenascin-C murine models with engineered tenascin-C levels were generated:
PNET insulinoma to study angiogenesis (Saupe et al., 2013, Cell Rep 5; Langlois et al., 2014, Oncotarget 5)
MMTV-NeuNT breast cancer to study immunity and metastasis (Sun et al., 2019, Mat Bio 83; Deligne et al., 2020, Cancer Immun Res 8; Spenle et al., 2020, Cancer Immun Res 8; Murdamoothoo et al., 2021, EMBO Mol Med 13)
Autochthonous NT193 breast cancer to study immune editing, TMT formation and TIL-Matrix-Retention (Sun et al., 2019, Mat Bio 83; Deligne et al., 2020, Cancer Immun Res 8; Murdamoothoo et al., 2021, EMBO Mol Med 13)
Carinogen-induced tongue oral squamous cell carcinoma (OSCC) to study matrix immune suppression (Spenle 2021, Cancer Immun Res 8)
Radiosensitive syngeneic tongue OSCC13 grafting to study matrix regulation of irradiation-induced tumor remission (Spenle et al., 2021, Front Immun 12)
AAV kidney disease (Anti neutrophil cytoplasmic antibody associated vasculitis) to study matrix regulation of kidney necrosis/sclerosis (Abou-Faycal et al., 2022, Mat Bio 106)
The laboratory showed that tenascin-C plays a Janus role in tumor angiogenesis by employing distinct molecular mechanisms thus promoting the formation of new blood vessels that are however leaky (Saupe et al., 2013, Cell Rep 5). The results have prognostic value in cancer and showed that already tenascin-C levels below the median (however highly exceeding tenascin-C levels in normal tissues) correlates with shorter patient survival as tenascin-C triggers cancer cell migration and metastasis by autocrine and paracrine mechanisms (Sun et al., 2018, Cancer Res 78; Sun et al., 2019, Mat Bio 83). The laboratory demonstrated that tenascin-C promotes the angiogenic switch as one of the AngioMatrix molecules that defines this switch (Langlois et al., 2014, Oncotarget 5; Rupp et al., 2016, Cell Rep 17; Radwanska et al., 2017, Sci Rep 7). The laboratory further showed that tenascin-C forms fibrillar tumor matrix tracks (TMT) together with fibronectin, laminin and other matrix molecules inside the tumor stroma, thereby generating biochemical niches for tumor, stromal and immune cells (Spenle et al., 2015, Cell Adh Migr 9). Using the novel immune competent tumor models with engineered tenascin-C expression furthermore allowed the team to discover so far unknown actions of tenascin-C in orchestrating tumor immunity. Tenascin-C induces and binds several chemokines thus generating a sticky substratum that retains tumor infiltrating leukocytes (TIL) in the stroma, representing the immune exclusion phenotype, thereby blocking TIL contact with the tumor cells. This TIL-Matrix-Retention mechanism can be targeted by inhibition of specific tenascin-C actions (Spenle et al., 2020, Cancer Immun Res 8; Deligne et al., 2020, Cancer Immun Res 8; Murdamoothoo et al., 2021, EMBO Mol Med 13) in particular with novel tenascin-C specific nanobodies (Dhaouadi et al., 2021, Front Immun 12) and the MAREMO peptides (Loustau et al., 2022, Mat Bio 108), altogether substantiating the concept of targeting matrix to improving immune checkpoint and anti-cancer therapy.