Biology subjects

Isacke, C. M.

Publications and source records attributed to Isacke, C. M..

3 recordsLinked to original sources

bioRxiv2020

Myeloid derived Oncostatin M reprogrammes cancer-associated fibroblasts and tumour cells promoting breast cancer progression

Cancer cells are constantly communicating with the surrounding tumour microenvironment (TME) and they hijack physiological cell interactions to overcome immune system surveillance and promote cancer progression1,2. However, the contribution of stromal cells to the reprogramming of the TME is not well understood. In this study we provide unprecedented evidence of the role of the cytokine Oncostatin M (OSM) as central node for multicellular interactions between immune and non-immune stroma and the epithelial compartment. We show that stromal expression of the OSM:Oncostatin M Receptor (OSMR) axis plays a key role in breast cancer progression. OSMR deletion in a multistage breast cancer model delays tumour onset, tumour growth and reduces metastatic burden. We ascribed causality to the stromal function of OSM axis by demonstrating reduced tumour burden of syngeneic tumours implanted in mice. Single-cell and bioinformatic analysis of murine and human breast tumours revealed that the expression of OSM signalling components is compartmentalized in the tumour stroma. OSM expression is restricted to myeloid cells, whereas OSMR expression is detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprograms fibroblasts to a more contractile and pro-tumorigenic phenotype, elicits the secretion of VEGF and pro-inflammatory chemokines (e.g. CXCL1 and CXCL16), leading to increased neutrophil and macrophage recruitment. In summary, our work sheds light on the mechanism of immune regulation by the tumour microenvironment, and supports that targeting OSM:OSMR interactions is a potential therapeutic strategy to inhibit tumour-promoting inflammation and breast cancer progression.

cancer biology↗

bioRxiv2020

Therapy-induced senescence in normal tissue promotes breast cancer metastasis

Disseminated tumour cells frequently exhibit a period of dormancy that renders them insensitive to targeting by chemotherapeutic agents, conversely the systemic delivery of chemotherapies can result in normal tissue damage. Using multiple mouse and human breast cancer models, we demonstrate that prior chemotherapy administration enhances metastatic colonisation and outgrowth. In vitro, chemotherapy treatment induces fibroblast senescence associated with a senescence associated secretory phenotype (SASP) that accelerates 3D tumour spheroid growth. These chemotherapy-treated fibroblasts, and their pro-tumourigenic function, can be effectively eliminated by targeting the anti-apoptotic protein BCL-xL. In vivo, chemotherapy treatment induces SASP expression in normal tissues, however the accumulation of senescent cells is limited and BCL-xL inhibitors are unable to reduce chemotherapy-enhanced metastasis. This likely reflects that chemotherapy-exposed normal tissues support metastatic colonisation via the secretion of pro-tumourigenic factors and remodelling of the extracellular matrix, but that damaged stromal cells do not enter a full BCL-xL-dependent senescence or switch their dependency to other anti-apoptotic BCL-2 family members. In summary, this study highlights the role of the metastatic microenvironment in controlling outgrowth of disseminated tumour cells and the need to identify novel therapeutic approaches to effectively limit the pro-tumourigenic effects of chemotherapy-induced normal tissue damage.

cancer biology↗

bioRxiv2020

Impairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis

Profiling studies have revealed considerable phenotypic heterogeneity in cancer-associated fibroblasts (CAFs) present within the tumour microenvironment, however, functional characterisation of different CAF subsets is hampered by the lack of specific markers defining these populations. Here we show that genetic deletion of the Endo180 (MRC2) receptor, predominantly expressed by a population of matrix-remodelling CAFs, profoundly limits tumour growth and metastasis; effects that can be recapitulated in 3D co-culture assays. This impairment results from a CAF-intrinsic contractility defect and reduced CAF viability which, coupled with the lack of phenotype in the normal mouse, demonstrates that upregulated Endo180 expression by a specific, potentially targetable CAF subset is required to generate a supportive tumour microenvironment. Further, characterisation of a tumour subline selected via serial in vivo passage for its ability to overcome these stromal defects provides important insight into how tumour cells adapt to a non-activated stroma in the early stages of metastatic colonisation.

cancer biology↗