Developing novel cancer therapeutics by functional interrogation of the nervous system

A PhD project for the 2022 doctoral clinical fellows programme with Leanne Li (primary supervisor, Crick), Ioanna Keklikoglou (Barts Cancer Institute/QMUL) and Rickie Patani (Crick/UCL)

Project description

Ioanna Keklikoglou

Lecturer & Group Leader, Barts Cancer Institute/QMUL

The course of cancer progression is dictated by the complicated interplay between cancer cell intrinsic factors and extrinsic environmental factors. Tumours are made up of both cancer cells and host cells that support the tumour’s growth. Interactions between the different types of cells in the tumour constantly shape the behaviour of the cancer cells and affect how the disease will progress. Therefore, in order to develop more efficacious cancer therapies, we need to understand how cancer cells communicate with the host or ‘stromal’ cells within the area directly around the tumour, called the tumour microenvironment. Furthermore, we also need to know how the tumour communicates with the rest of the body. 

In particular, accumulating evidence has indicated that cancer and the nervous system bear a much closer, entangled relationship than had been appreciated. Changes of the innervation landscape, significantly impacting cancer progression, have been observed in many cancer types. However, perturbations of neural activity have yielded incoherent results in distinct cancer types, and sometimes even in the same cancer type across different studies. This variability may be due to the limitations in the currently employed methodologies: the composition of cancer-innervating neuronal populations has not been extensively profiled, and the standard methods used to manipulate neural activity, such as surgical denervation and pharmacological treatment, lack specificity and selectivity in both the location of the perturbation and types of neurons affected, which complicates the interpretation of results.

We are interested in elucidating the interactions between cancer and the nervous system. In particular, we aim to reveal how tumour innervation may affect cancer progression, and whether interfering with such a crosstalk could provide novel inroads for cancer therapy.

The doctoral project will develop around the two key questions: Does the presence of a tumour rewire the nervous system, both locally and remotely? Can we treat cancers by manipulating the nervous system?

We use a variety of highly translational genetically-engineered mouse models (GEMMs) of cancer [1-3] and GEMM-derive cancer cell lines as our principal platforms of investigation. We will employ a wide range of advanced techniques to interrogate the role of innervation in tumour progression, including microCT, MRI, ultrasound, advanced microscopy imaging, optogenetics [4], chemogenetics, microfluidic devices, intravital imaging, iPSC studies [5] etc. 

Clinicians who are interested in cancer research or neuroscience, who are passionate in understanding the basic mechanisms of cancer progression and its interaction with the nervous system, and who are enthusiastic about developing novel therapeutic options for cancer patients are welcome to join us.

The partner institution for this project is Barts Cancer Institute/QMUL.
 

References

  1. Li, L., Ng, S. R., Colon, C. I., Drapkin, B. J., Hsu, P. P., Li, Z., . . . Jacks, T. (2019). Identification of DHODH as a therapeutic target in small cell lung cancer. Sci Transl Med 11.
  2. Li, L., Zeng, Q., Bhutkar, A., Galvan, J. A., Karamitopoulou, E., Noordermeer, D., . . . Hanahan, D. (2018). GKAP Acts as a Genetic Modulator of NMDAR Signaling to Govern Invasive Tumor Growth. Cancer Cell 33: 736-751 e735. 
  3. Li, L. and Hanahan, D. (2013). Hijacking the neuronal NMDAR signaling circuit to promote tumor growth and invasion. Cell 153: 86-100. 
  4. Venkatesh, H. S., Morishita, W., Geraghty, A. C., Silverbush, D., Gillespie, S. M., Arzt, M., . . . Monje, M. (2019). Electrical and synaptic integration of glioma into neural circuits. Nature 573: 539-545. 
  5. Robinson, H. P. C. and Li, L. (2017). Autocrine, paracrine and necrotic NMDA receptor signalling in mouse pancreatic neuroendocrine tumour cells. Open Biol 7.