Closed: Triple Negative Breast cancer control of the immune tumour microenvironment in metastasis
Project background
Metastasis, the spread of cancer to secondary organs, accounts for approximately 90% of cancer-related deaths mainly due to resistance to conventional treatments and organ failure. Unfortunately, our understanding of metastasis evolution, from its onset to treatment resistance, remains limited. Although natural selection acts on phenotypes, cancer research has traditionally focused on genotype alterations. Despite extensive efforts, specific genetic alterations that would confer metastatic functions have not yet been identified. In addition, the regulation of a cell´s phenotypic output is multi-layered, with both transcriptional and epigenetic mechanisms playing key roles. To address these crucial gaps in knowledge, we have established the ADAPTMET consortium.
The goal of the consortium is to bolster basic research on metastatic cancers, ultimately influencing drug development and improving the clinical standard of care. This initiative aligns with the solution-oriented missions of Horizon Europe, with cancer being one of its priority areas.
Cancer progression involves two central capabilities: invading the stroma and adapting to hostile environments when colonising secondary organs. The vasculature plays a crucial role in tumour progression and therapy response, sharing signalling and metabolic pathways with cancer cells. Other stromal cells such as fibroblasts exhibit similar behaviour whereas the immune cell repertoire may support or limit progression owing to a complex integration of systemic and local cues. Our approach combines state-of-the-art experimental systems with clinical analyses to dissect the mechanisms of tumour-stroma interaction in metastasis.
Extensive experimental evidence suggests that the tumour microenvironment and metastatic niches are potential targets for therapy. To this end, endothelial, fibroblast and immune cell driven engineered mouse models within this consortium represent unique opportunities.
In our group based at ICR, we have previously found that TNBC primary tumours in which we block Myosin driven cytoskeletal dynamics generate a less supportive TME (specifically fibroblasts and macrophages significantly change).
We will explore if similar mechanisms are operative during metastatic organ colonisation and outgrowth in the lung and in the brain- which are two key metastatic sites for TNBC.
We aim to find key vulnerabilities of metastatic TNBC cells that could be clinically targeted.
Funding details: The candidate will receive a monthly salary of £4,574 (subject to tax and National Insurance deductions), which includes both a living allowance and a mobility allowance, for a duration of 36 months. Additionally, candidates with a family may be eligible for a monthly family allowance of £430 (also subject to tax and National Insurance deductions), provided they meet the eligibility criteria for the MSCA family allowance.
Project aims
This project will focus on:
- Characterisation on how Myosin driven cytoskeletal dynamics blockade generates a less supportive TME in metastasis.
- Studying how these adaptive mechanisms operate during metastatic organ colonisation (early lung colonisation and micro-metastasis stages) and outgrowth (macro-metastasis development)
- Using gained knowledge to identify therapeutic vulnerabilities of amoeboid metastatic TNBC cells that could be clinically targeted. • We will use patient tissue material to identify micro-niches (in the lung and the brain) that are supportive of metastatic outgrowth and that are relevant in the human setting.
- Planned secondment(s): to understand how cancer cell cytoskeletal dynamics may alter microglia and brain macrophages, the student will spend a period at Prof Johanna Joyce's lab at the University of Lausanne
Further details & requirements
Aim and overview
Metastasis is the principal cause of death in many cancers and is in part driven by a subset of aggressive cells adopting an amoeboid cellular state, enabling them to survive, migrate away from primary tumours and colonise challenging microenvironments while escaping current therapeutic approaches.
Abnormal cell migration is characteristic of disseminating cancer cells and is driven by cytoskeletal remodelling. Epithelial cells become motile by undergoing epithelial-to-mesenchymal transition (EMT), while mesenchymal cells increase migration speed by adopting amoeboid features. We have described how amoeboid behaviour is not merely a migration mode but a cellular state - within the EMT continuum - by which cancer cells survive, invade and colonise challenging microenvironments.
We found an enrichment in amoeboid cells at the border of primary tumours and at the border of metastatic lesions in several tumour types. The tumour edge represents a unique structure in which cancer cells are more exposed to matrix, stromal cells and immune infiltrate. Invading and disseminating cells must overcome immune cell attack in their way to a secondary site, so they develop immunosuppressive strategies.
In this project we will focus on studying the interactions that amoeboid cancer cells establish with the metastatic niche, with a particular focus on TNBC metastasizing to lung and brain and the specific interactions with immune cells in those organs.
For this purpose, 3D co-culture systems and organoids, mouse models and patient samples will be used to dissect the specific crosstalk between amoeboid cancer cells and the TME supporting their metastatic abilities.
The specific objectives of this PhD will be:
i) Characterisation on how Myosin driven cytoskeletal dynamics blockade generates a less supportive TME in metastasis
For this purpose, we will study the secretome of highly metastatic TNBC cells and we will manipulate using ROCKMyosin II inhibitors (we will use cytokine arrays and mass spectrometry to analyse proteins and metabolites). Both classical secretion and EV secretion will be compared, and top candidate secreted factors (proteins or metabolites) will be interrogated for the possible effects on monocyte/macrophage fate and function.
ii) Studying how these adaptive mechanisms operate during metastatic organ colonisation
We will compare early lung colonisation and micro-metastasis stages with metastatic outgrowth or macro-metastasis development. We have generated single cell data (VSM lab unpublished) on the TME of murine TNBC in the early and late stages of lung colonisation and outgrowth. We will generate a similar dataset after brain colonisation/outgrowth and will compare how innate immune responses are conserved/different after manipulation of the Myosin II cytoskeleton in cancer cells. We will study the brain TME in more detail since this is a very challenging microenvironment but also TNBC that has metastasized to the brain is very difficult to treat. The student will also have a secondment at the University of Lausanne under the guidance of Prof Johanna Joyce who is an integral member of ADAPTMET. Since we have a special interest in tumour associated macrophages, we will exploit Prof Joyce’s expertise in the brain TME to understand how cytoskeletal dynamics may alter microglia and brain macrophages.
iii) Using gained knowledge from all above objectives, we will identify therapeutic vulnerabilities
We will study vulnerabilities of amoeboid metastatic TNBC cells and the myeloid populations they recruit and/or corrupt- that could be clinically targeted. Using mouse models, we will validate how depletion of the most promising protein/metabolite candidates secreted by metastatic cancer cells (and regulated by ROCK-Myosin II) affect metastatic success and innate immune responses.
iv) We will use patient tissue material provided by Prof Andrew Tutt to identify pro-metastatic micro-niches
We will compare tissue sections from the primary tumour (invasive vs non-invasive areas) and sections from lung and brain metastasis. We will validate specific cancer cell-macrophage interactions with appropriate immunohistochemical approaches.
The overarching aim of this PhD is to study how metastatic breast cancer cells communicate with myeloid cells that support their survival and growth in secondary organs such as the brain and the lung. The knowledge we will gain will be used to design future anti-metastasis approaches.
Only applicants who satisfy the following mobility rule are eligible to apply: Applicants must not have resided or carried out their main activity (work, studies, etc.) in the UK for more than 12 months in the 36 months immediately before their recruitment date.Note: the ICR’s standard minimum entry requirement is a relevant undergraduate Honours degree (First or 2:1)
Pre-requisite qualifications of applicants:
At least a 2:1 degree in a relevant scientific subject Some experience of cell biology and animal experimentation is preferred but exceptional candidates in other disciplines will be considered.
Intended learning outcomes:
- Cell biology: tissue culture, 3D biology and microscopy techniques
- Mouse in vivo work
- Tissue pathology collection and analysis
- Computational and quantitative skills: Use of in silico tools for data analysis
- Communication: Ability to present work verbally and in writing to a multidisciplinary audience, including writing and submitting of papers to high impact peer-reviewed journals
- Teamwork: experience of working in a multidisciplinary research team
[1] Samain R, Maiques O, Monger J, Lam H, Candido J, George S, Ferrari N, KohIhammer L, Lunetto S, Vilardell F, Olsina JJ, Matias-Guiu X, Sarker D, Biddle A, Balkwill FR, Eyles J, Wilkinson RW, Kocher HM, Calvo F, Wells CM, Sanz-Moreno V (2023) CD73 controls Myosin II driven invasion, metastasis and immunosuppression in amoeboid pancreatic cancer cells. Science Advances https://doi.org/10.1126/sciadv.adi0244
[2] Crosas-Molist E, Graziani V, Maiques O, Pandya P, Monger J, Samain R, George SL, Malik S, Salise J, Morales V, Le Guennec A, Atkinson RA, Marti RM, Matias-Guiu X, Charras G, Conte MR, Elosegui-Artola A, Holt M, Sanz-Moreno V (2023) AMPK is a Mechano-Metabolic Sensor Linking Mitochondrial Dynamics to Myosin II Dependent Cell Migration. Nature Communications https://doi.org/10.1038/s41467-023-38292-0
[3] Barcelo J, Samain R, Sanz-Moreno V (2023) Clinical utility of ROCK inhibitors in cancer. Trends in Cancer. https://doi.org/10.1016/j.trecan.2022.12.001
[4] Jung-Garcia Y, Maiques O, Monger J, Rodriguez-Hernandez I, Fanshawe B, Domart MC, Renshaw M, Marti RS, Matias-Guiu X, Collinson LM, Sanz-Moreno V* & Carlton JG* (2023) *co-corresponding co-senior authors. LAP1 regulates nuclear plasticity to enable melanoma constrained migration and invasion. Nature Cell Biology https://doi.org/10.1038/s41556-022-01042-3
[5] Graziani V, Rodriguez-Hernandez I, Maiques O, Sanz-Moreno V (2022) The amoeboid state as part of the epithelial to mesenchymal transition program. Trends in Cell Biology. https://doi.org/10.1016/j.tcb.2021.10.004
[6] Crosas-Molist E, Samain R, Kohlhammer L, Orgaz JL, George SL, Barcelo J, Maiques O, Sanz-Moreno V (2022) Rho GTPase signalling in Cancer Progression and Dissemination Physiological Reviews. https://doi.org//10.1152/physrev.00045.2020
[7] Perdrix-Rosell A, Maiques O, Martin JA, Chakravarty P, Ombrato L, Sanz Moreno V*, Malanchi I* (2022) *co-corresponding co-senior authors. Early functional mismatch between breast cancer cells and their tumour microenvironment suppresses long term growth. Cancer Letters https://doi.org/10.1016/j.canlet.2022.215800
[8] Rodriguez-Hernandez I, Maiques O, Cantelli G, Perdrix A, Monger J, Fanshawe B, Karagiannis S, Santacana M, Mathias Guiu X, Maria Marti R, Orgaz JL, Fruhwirth G, Malanchi I, Sanz-Moreno V (2020) WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion. Nature Communications. https://doi.org/10.1038/s41467-020-18951-2
[9] Orgaz JL, Crosas-Molist E, Sadok A, Perdrix-Rosell A, Maiques O, Monger J, Rodriguez-Hernandez I, Mele S, Georgouli M, Bridgeman V, Karagiannis P, Pandya P, Cantelli G, Boehme L, Wallberg F, V Tape C, Karagiannis SN, Malanchi I, Sanz-Moreno V (2020) Myosin II reactivation and Cytoskeletal remodelling as a hallmark and a vulnerability in melanoma resistance. Cancer Cell. https://doi.org/10.1016/j.ccell.2019.12.003 [10]Georgouli M, Herraiz C, Crosas-Molist E, Fanshawe B, Maiques O, Perdrix A, Pandya P, Cantelli G, Rodriguez-Hernandez I, Karagiannis P, Lam H, Josephs D, Matias-Guiu X, Marti RM, Nestle FO, Orgaz JL, Malanchi I, Fruhwirth GO, Karagiannis SN, Sanz-Moreno V (2019) Regional activation of Myosin II in cancer cells drives tumour progression via a secret