Rosalind and Morris
Goodman Cancer
Institute Principal
Investigators
- Understanding the molecular mechanisms that underpin pro-inflammatory hematopoiesis and how this can be targeted to reduce systemic inflammation and cancer progression
- Unravelling the impact of estrogen signaling on hematopoiesis and how estrogen deficiency (menopause) leads to chronic inflammation
Inflammation is a hallmark of cancer: tumours hijack blood cell development (haematopoiesis), skewing bone marrow output towards the myeloid lineage leading to tumour-supporting chronic systemic inflammation. Conversely, chronic inflammatory conditions can also predispose individuals to developing tumours, leading to a bidirectional relationship between inflammation and cancer.
Myeloid cells, including monocytes, neutrophils, and their bone marrow progenitors, are highly plastic, rapidly integrating local and systemic cues such as pro-inflammatory mediators. Chronic systemic inflammation functionally reprogrammes these cells towards a tumour-supporting state and this “education” occurs on multiple levels: during their development in the bone marrow; within primary tumours; and in shaping the (pre-)metastatic niche.
Using spontaneous pre-clinical mouse models that closely mimic human breast and ovarian cancer progression, combined with patient samples, we aim to uncover the molecular and cellular mechanisms driving chronic inflammatory myeloid cell education. By understanding how these processes promote tumour- and metastasis-supporting inflammation, we aim to identify novel therapeutic strategies for breast and ovarian cancer patients.
What we are
currently
working on
It is increasingly recognised that the tumour macroenvironment – extending beyond the tumour microenvironment and incorporating systemic components such as the immune system - plays a critical role in tumour initiation, progression and metastatic spread. Inflammation is involved in every stage of cancer progression from initiation to metastatic spread. All circulating blood cells, including inflammatory cells develop from rare, self-renewing haematopoietic stem cells (HSCs) that differentiate through a series of steps. This system is a highly dynamic and adapts quickly to inflammatory signals, boosting the production of myeloid cells during inflammation or injury to meet demand. In cancer, primary tumours release inflammatory signals that affect distant tissues including the bone marrow (BM). These signals drive expansion and polarisation of myeloid cells, shifting their roles to support tumour progression, in addition, persistent tumour-driven inflammation can also lead to premature release of immature myeloid cells from the BM into the circulation. Causally, systemic accumulation and polarisation of myeloid cells has been shown to play many roles in disease progression from suppression of anti-tumour immune responses to contributing to the development of a pre-metastatic niche.
Our aims are to understand how different pro-inflammatory signals change haematopoiesis at a molecular, cellular and spatial level and how this bone marrow education changes the functionality of myeloid cells in the periphery.
- 1) Understanding and disrupting primary tumour induced skewing of haematopoiesis to reduce metastatic spread Different tumours produce different pro-inflammatory mediators which can lead to different lineage fate decisions. We are working to investigate how different inflammatory signals influence bone marrow output, with a particular focus on the transcription factors that control lineage specification within the myeloid compartment. Using genetically modified mouse models (GEMMs) of breast and ovarian cancer, we aim to understand how primary tumours influence local bone marrow cues that organise and control myelopoiesis. By deepening our understanding of how primary tumours alter control of myelopoiesis, we aim to uncover novel targets for normalising haematopoietic output in tumour-bearing hosts to reduce tumour-induced systemic inflammation and metastatic spread and potentially improve response to immune checkpoint blockade.
- 2) Oestrogen signalling in haematopoiesis Sex differences in the immune system are well documented with females exhibiting stronger immune responses and oestrogen is widely considered to have a “protective” effect in pre-menopausal women against chronic inflammatory conditions. However, this advantage diminishes after menopause, suggesting that hormonal signalling plays an important role. Haematopoietic stem cells (HSCs) express oestrogen receptors (ERs) and oestrogen influences their proliferation, differentiation, and survival of HSCs and progenitor cells. We are working to understand how normal, physiological variations in oestrogen levels impact haematopoiesis, lineage fate decisions and myeloid cell function during an adult biological female’s lifespan. Combining analysis of mouse models and human blood samples, we are exploring how oestrogen-deficiency reshapes immune cell development and can drive tumour-promoting chronic, systemic inflammation. In the future, we will expand our analysis to understand how targeted hormone therapies for ER+ breast cancer (such as aromatase inhibitors) impact the immune system, in particular myeloid cells. This work will provide insights into the intersection of hormonal signalling, immune regulation and cancer progression.
- 3) Long term consequences of myelosuppressive chemotherapy Chemotherapy is widely used to treat breast and ovarian cancer targeting rapidly dividing cells. However, this includes immune progenitors making them highly sensitive to killing by chemotherapeutics. Specifically, myeloid progenitors which continually replenish inflammatory cells such as monocytes and neutrophils are heavily suppressed by many chemotherapeutic agents. In the short-term this myelosuppression can lead to increased risk of bacterial infection. In the long term, immune cell numbers broadly recover, however there is limited data on the long-term functional consequences of this therapy-induced myelosuppression. Emerging evidence suggests that myelosuppressive chemotherapy can induce somatic mutations in hematopoietic stem and progenitor cells (HSPCs) resulting in clonal haematopoiesis (CH). CH is increasingly recognized not only for its association with haematological malignancies but also for its link with immune dysfunction, particularly in the context of inflammatory diseases. However, CH may not be the only mechanism by which myeloablative chemotherapy leads to immune dysfunction. Our research focuses on understanding chemotherapy-induced genetic and epigenetic changes in HSPCs and mammary gland macrophages that lead to breast cancer-promoting local and systemic chronic inflammation. Deeper, mechanistic understanding of the consequences of chemotherapy on inflammatory cells will provide insight to how chemotherapy-induced changes lead to immune dysfunction and provide insight into whether immune dysfunction contributes to resistance to immune checkpoint blockade in heavily pre-treated patients.
- Member, Rosalind and Morris Goodman Cancer Institute (2024-present)
- Assistant Professor, Department of Microbiology and Immunology (2024-present)
Our team
Major discoveries
- 2023
Eosinophils and CD4 T cells cooperate to enhance response to immune checkpoint blockade in breast cancer
https://www.sciencedirect.com/science/article/pii/S153561082200561X
Research Partners
Get in touch
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Montreal, Quebec
Office: 415
Lab:
T. 514 396 2850
T.
F.
hannah.garner@mcgill.ca
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