Antagonising tumour microenvironment-mediated drug resistance in pancreas adenocarcinoma

Primary supervisor: Ingo Ringshausen, UCL

Secondary supervisor: Kairbaan Hodivala-Dilke, Queen Mary University of London

Project

Project background and description:
Over the past decade, an increasing amount of evidence has demonstrated that interactions between tumour cells and their environment are critical for transformation and disease progression, but also determine response to cancer therapies. Therefore, antagonising the interactions between tumour and non-malignant cells is an alternative and orthogonal approach to treat cancer. Our group has recently shown that malignant cells from patients with haematological malignancies activate and reprogram mesenchymal stroma cells of the tumour microenvironment, which in turn protect cancer cells from spontaneous and drug-induced apoptosis. We demonstrate that this process is strictly dependent on the activation of protein kinase C (PKC)- signalling in stroma cells [1]. Antagonising PKC-signalling through genetic interference or small molecule inhibitors prolonged the life span of leukaemia bearing mice [2]. This work has led to a patent-application as well to a clinical trial, illustrating the translational impact of this new line of research.

This project builds on ours and other data indicating that PKC-activity in non-malignant cells is important for (1) disease progression of breast [3] and pancreas carcinoma [unpublished], (2) tumour-angiogenesis [4] and (3) that endothelial cells are crucial for the protection of cancer cells from chemotherapeutic drugs [5].
This interdisciplinary project will address the role of PKC-signalling in mesenchymal and endothelial cells in pancreas adenocarcinoma. Exploiting established 2D and 3D-co-culture models using primary mouse derived mesenchymal and endothelial cells in combination with in vivo models (GEMMs, PDX-mouse models) and single cells analyses, this project will address the following questions:

(1) Which subset(s) of stroma & endothelial cells require PKC-activity for tumour-progression and angiogenesis. A particular focus of the project will be to identify how genetic and pharmacological inhibition of PKC-dependent signalling events skews the differentiation of cancer-associated fibroblasts (CAFs) and affects angiogenesis. The applicant will apply single cell sequencing/ transcriptomics and immunofluorescence to address this aim

(2) Which signalling pathways drive the communication between tumour cells and stroma & endothelial cells. Through mass spectrometry/ image mass cytometry and RNA-sequencing we will identify signalling molecules essential for the interaction between stroma-, endothelial- and cancer cells and how this affects responses to therapies.

(3) Identifying novel therapies to treat pancreas cancer. In collaboration with the Crick Institute, the applicant will test novel kinase inhibitors to target PKC-signalling in the tumour-stroma/endothelial cell- interaction. In addition, alternative therapeutic targets identified through aims 1 and 2, can be tested through genetic approaches (conditional knock out models) or pharmacologically in established in vitro or in vivo assays.

Ultimately, this project aims to identify novel therapies to treat pancreas adenocarcinomas through antagonising pro-tumorigenic signals from the tumour microenvironment.

Candidate background

The project is particularly suitable for candidates with a strong interest in the tumour microenvironment, molecular biology and translational cancer research who would like to pursue an academic career. Previous wet lab experience, particularly of flow cytometry, molecular biology and primary cell culture are highly desirable but not essential.

Potential Research Placements

1. Kairbaan Hodivala-Dilke, Barts Cancer Institute, Queen Mary University of London
2. Andrew Finch, Barts Cancer Institute, Queen Mary University of London
3. Alan Ramsey, King’s College London

References

1. Lutzny, G. et al. Protein kinase C-β-dependent activation of NF-κB in stromal cells is indispensable for the survival of chronic lymphocytic leukemia B cells in vivo. Cancer cell 23, 77-92 (2013).
2. Park, E. et al. Stromal cell protein kinase C-β inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance. Science Translational Medicine 12, eaax9340 (2020).
3. Wallace, J. A. et al. Protein Kinase C Beta in the Tumor Microenvironment Promotes Mammary Tumorigenesis. Frontiers Oncol 4, 87 (2014).
4. Yoshiji, H. et al. Protein kinase C lies on the signaling pathway for vascular endothelial growth factor- mediated tumor development and angiogenesis. Cancer Res. 59, 4413-8 (1999).
5. Cappelli, L. V. et al. Endothelial cell-leukemia interactions remodel drug responses, uncovering T-ALL vulnerabilities. Blood 141, 503-518 (2023).