Understanding myeloid heterogeneity in premetastatic niches following cytotoxic therapy
Primary Supervisor: Dr Ioanna Keklikoglou, Barts Cancer Institute, Queen Mary University of London
Secondary Supervisor: Dr Chris Tape, UCL Cancer Institute, University College London
Tertiary Supervisor: Prof Frances Balkwill, Barts Cancer Institute, Queen Mary University of London
Chemotherapy is the standard of care for the management of locally advanced, invasive breast cancer. However, tumours often develop resistance to chemotherapy, while those that initially respond to the treatment eventually relapse, thus increasing the likelihood of metastasis formation. The tumour microenvironment has a fundamental role in fostering tumour resistance to chemotherapy regimens. Tumour-associated macrophages (TAMs) that infiltrate primary tumours limit the chemotherapeutic efficacy in mouse models of breast cancer[1]. Yet, the role of macrophages in mediating chemoresistance at pre-metastatic niches and metastatic tumours is so far poorly understood. We have recently shown that neoadjuvant chemotherapy enhances the propensity of breast cancer cells to metastasize via the induction of tumour-derived pro-metastatic extra-cellular vesicles (EVs). Importantly, we found that chemotherapy-elicited EVs interact with pulmonary endothelial cells and induce a pro-inflammatory response in the pre-metastatic niche, leading to enhanced accumulation of Ly6C+CCR2+ monocytes which support metastatic seeding[2]. In spite of growing interest, this research field is still in its infancy: although previous studies have elucidated the role of CCR2+ monocytes in metastasis by facilitating cancer cell extravasation and promoting cell survival[3], how these cells and other metastasis-associated monocytic subpopulations respond to chemotherapy remains unknown.
This project will unravel how chemotherapy alters monocyte/macrophage function to support metastatic seeding and growth. By exploiting state-of-the art mouse models of cancer, pre-metastatic niche labelling tools, as well as quantitative molecular and cellular approaches, the student will elucidate the role of the non-malignant cellular components in pre-metastatic niches in supporting/facilitating metastatic cancer cell seeding and tumour growth in chemotherapy treated mouse models of breast cancer. The monocyte/macrophage subpopulations that facilitate metastasis formation in response to chemotherapy and the molecular pathways involved in this process will be identified by profiling at the single-cell level the transcriptomes of lung microenvironments exposed to chemotherapy. Furthermore, the origin of metastasis-associated macrophage subpopulations will be investigated using in vivo lineage tracing tools and bone marrow transplantation experiments. To understand how chemotherapy alters signalling and cell communication in the lung pre-metastatic niche of tumour-bearing mice, cell-specific signalling technologies will be employed, including heterocellular proteomics and single-cell mass cytometry[4]. Using either genetic or pharmacological approaches we will interrogate the mechanistic role of selected targets in re-programming metastasis-associated macrophages. Ultimately, this project may provide targets for therapeutic intervention.
The ideal candidate should have a strong background in molecular and cellular biology and previous laboratory experience. Experience in basic molecular biology and biochemistry techniques (qPCR, ELISA, Western Blot) as well as cell culture and flow cytometry is preferred. Previous experience with mouse models and analysis of functional genomic datasets (i.e. using R programming) is desired, but not mandatory.
Potential research placements
1. Dr Chris Tape (UCL Cancer Institute) – Single-cell post-translational modification signalling networks and mass spectrometry (CyTOF).
2. Dr Mirjana Efremova (Barts Cancer Institute) – Analysis of scRNA-seq data.
3. Dr Erik Sahai (The Francis Crick Institute) – Intravital imaging.
The funding for this studentship covers students with home tuition fee status only. For more information on home tuition fee status please visit the UKCISA website. Please note that we will only be able to offer studentships to candidates that have home tuition fee status or provide evidence that they can fund the international portion of the tuition fee from external sources (i.e. not self-funded).
References
1. Hughes, R. et al., Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy. Cancer Res. 75, 3479–3491. doi: 10.1158/0008-5472.CAN-14-3587. (2015)
2. Keklikoglou, I., et al., Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models. Nat. Cell Biol. 21, 190–202. doi: 10.1038/s41556-018-0256-3. (2019)
3. Kitamura, T. et al., CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J. Exp. Med. 212, 1043–1059. doi: 10.1084/jem.20141836. (2015)
4. Qin, X., et al., Cell-type-specific signalling networks in heterocellular organoids. Nat. Methods. 17, 335-342. doi: 10.1038/s41592-020-0737-8. (2020)