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CXCR3-expressing metastasis-initiating cells induce and exploit a fibroblast niche in the lungs to fuel metastatic colonization

Maren Pein, Jacob Insua-Rodriguez, Jasmin Meier, Tsunaki Hongu, Lena Wiedmann, Marieke A.G. Essers, Hans-Peter Sinn, Saskia Spaich, Marc Sutterlin, Andreas Schneeweiss, Andreas Trumpp, Thordur Oskarsson

Preprint posted on February 11, 2019 https://www.biorxiv.org/content/10.1101/546952v1

A new place to call home: disseminated cancer cells fleece lung fibroblasts to fuel a metastatic niche

Selected by Julija Hmeljak

 

BACKGROUND

Despite significant progress, metastasis remains the leading cause of mortality in cancer patients. Acquiring the ability to successfully metastasise to distal sites is a crucial, and not yet completely understood, stage in a cancer’s evolution. To do so, cancer cells must successfully leave the primary tumour site, survive in the bloodstream, invade the receiving tissue and establish a colony from which a new complex tumour will arise (Blomberg et al., 2018). The final step in this process, establishing a cancer cell colony within a secondary organ, requires significant changes to both the disseminated cancer cells and to the receiving stroma. A new preprint by the Oskarsson group explores the molecular crosstalk that leads to the successful establishment of breast cancer metastasis in lung tissue.

 

KEY FINDINGS

The authors injected GFP/luc-tagged breast cancer cells into the bloodstream of immunodeficient mice to induce lung metastases. They then performed a series of elegant experiments to show that metastasizing (disseminated) breast cancer cells evoke significant changes to lung fibroblasts, resulting in a niche that supports the establishment of a secondary tumour. These changes are mediated via an inflammatory signalling loop, whereby a specific subset of disseminated breast cancer cells excrete interleukin-1α and 1β to activate lung fibroblasts and push them towards a tumour-supportive phenotype, mainly by triggering an IL-1 receptor signalling-mediated expression of the chemokines CXCL9 and 10. Intriguingly, the same subset of disseminated breast cancer cells expresses the CXCR3 receptor, which binds CXCL9/10, indicating that metastasis-initiating cells are able to both induce and respond to molecular changes in reactive fibroblasts. This paracrine signalling remodels the receiving stroma and promotes the successful establishment of breast cancer metastases in the lung.

 

The authors’ model of the interaction between JNK-active breast cancer cells and IL-1-responsive fibroblasts. These reactive fibroblasts excrete the CXCL9 and 10 ligands, which bind to CXCR3 on the cancer cells to activate pro-metastatic signalling. Credit Pein et al., 2019: doi: http://dx.doi.org/10.1101/546952. Reproduced with permission from the authors. All rights reserved.

 

 

WHY I CHOSE THIS PREPRINT

The authors have built upon their previous work on the role of JNK signalling in breast cancer metastasis (Insua-Rodriguez et al., 2018), and have performed rigorous and well-controlled experiments providing interesting mechanistic insight into the cancer cell-stroma crosstalk. Studies of fibroblast interactions in the tumour microenvironment have predominantly focused on primary tumours (LeBleu and Kalluri, 2018). However, this work explores a less well understood aspect of the tumour microenvironment – the metastatic niche.

 

FUTURE PROSPECTS AND OPEN QUESTIONS

As the authors discuss in their conclusion, the role of CXCR3 signalling in cancer is complex, as it modulates the immune microenvironment. Although directly blocking the CXCR3 receptor may reduce the metastatic potential of this subset of highly metastatic breast cancer cells, it may have unintended consequences for T cell function and for antitumour immunity.

Are there any known actionable targets in the signalling pathway downstream of CXCR3?

Do you know if there are any recurrent (activating) mutations in CXCR3 in human cancers (e.g. from ICGC/TCGA cohorts)?

 

References:

Blomberg et al. (2018) Immune regulation of metastasis: mechanistic insights and therapeutic opportunities. Dis Model Mech. Oct 24;11(10).

Insua-Rodríguez Jet al. (2018) Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis. EMBO Mol Med. Sep 6: e9003. 

LeBleu and Kalluri (2018) A peek into cancer-associated fibroblasts: origins, functions and translational impact. Dis Model Mech.  Apr 19;11(4).  

 

Posted on: 5th March 2019 , updated on: 25th March 2019

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  • Author's response

    Maren Pein and Thordur Oskarsson shared

    Many thanks for highlighting our work! The questions that you raised are very good and we hope to provide some insights below.

    Questions:

    As the authors discuss in their conclusion, the role of CXCR3 signalling in cancer is complex, as it modulates the immune microenvironment. Although directly blocking the CXCR3 receptor may reduce the metastatic potential of this subset of highly metastatic breast cancer cells, it may have unintended consequences for T cell function and for antitumour immunity.

    • The role of CXCR3 in cancer progression is certainly complex. CXCR3 is expressed in different cell types of the tumor stroma, including immune cells such as effector T lymphocytes, NK cells and others1. CXCR3 signaling has been shown to be required for recruitment of CD4+ or CD8+ T cells and NK cells that are important for anti-tumor immunity2. However, CXCR3 also plays a role in the recruitment of monocytes/macrophages and regulatory T cells (Tregs) that can blunt anti-tumor immune responses and promote tumor progression1,3. Therefore, the balance between pro- and anti-tumor immune reactions in metastasis may significantly influence the response to CXCR3 inhibition. With this in mind, distinct cancer entities may respond differently to CXCR3 interference. Our study and work of others4 show that systemic CXCR3 inhibition represses metastatic colonization of the lung in syngeneic mouse models of breast cancer. The results suggest that blocking CXCR3 signaling may be a useful strategy to consider against breast cancer metastasis. Further studies are needed to determine whether this also applies to other cancer entities.

     

    Are there any known actionable targets in the signalling pathway downstream of CXCR3?

    • CXCR3 can induce a number of different signaling pathways, including PI3K-AKT, MAPK and phospholipase C5. The CXCR3 axis is recognized to be context-dependent. However, cell-type specificity of CXCR3-mediated signaling is not well understood. Therefore, actionable targets downstream of CXCR3 that are specific for cancer cells are currently not available. Identifying such targets would be particularly useful in those cancers where CXCR3-dependent immune response is crucial to restrain cancer growth. Our findings show that CXCR3-mediated interactions between metastasis-initiating cells and fibroblasts are driven by JNK-induced interleukin-1 in the cancer cells leading to production of CXCL9/10 in fibroblasts. Thus, JNK interference may represent an alternative strategy to target this crosstalk.

     

    Do you know if there are any recurrent (activating) mutations in CXCR3 in human cancers (e.g. from ICGC/TCGA cohorts)?

    • Mutations in the CXCR3 gene are generally rare in human tumors and recurrent mutations (activating or inhibiting) have not been identified. However, overexpression of the gene is often observed in aggressive cancer cells. Furthermore, our results indicate that CXCR3 is heterogeneously expressed within breast cancer cell populations and is linked to metastasis-initiating ability.

     

    References

    1. Susek KH, Karvouni M, Alici E, Lundqvist A. (2018) The Role of CXC Chemokine Receptors 1-4 on Immune Cells in the Tumor Microenvironment. Front Immunol. 9:2159.
    2. Barreira da Silva R, Laird ME, Yatim N, Fiette L, Ingersoll MA, Albert ML. (2015) Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nat Immunol. 16:850-8.
    3. Butler KL, Clancy-Thompson E, Mullins DW. (2017) CXCR3+ monocytes/macrophages are required for establishment of pulmonary metastases. Sci Rep. 7:45593.
    4. Walser TC, Rifat S, Ma X, Kundu N, Ward C, Goloubeva O, Johnson MG, Medina JC, Collins TL, Fulton AM. (2006) Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer. Cancer Res. 66:7701-7.
    5. Billottet C, Quemener C, Bikfalvi A. (2013) CXCR3, a double-edged sword in tumor progression and angiogenesis. Biochim Biophys Acta. 1836:287-95.

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