Research

My lab aims to understand the alterations in metabolism that take place in cancer and investigate whether extrinsic factors, such as diet, influence cancer metabolism and disease trajectory. We then want to uncover whether these dependencies can be exploited therapeutically and whether dietary modulation can increase their efficacy.

The altered metabolism of tumor cells is not a new concept in cancer biology. In the early 1920s, Otto Warburg established that cancerous tissues have an altered metabolism compared to their non-tumorigenic counterparts and satisfy their bioenergetic demands by shifting from oxidative phosphorylation (OXPHOS) to glycolysis. Although this shift decreases the efficiency of ATP production per molecule of glucose, it favors the shuttling of metabolic intermediates to biosynthetic processes required for macromolecule biosynthesis, i.e. production of proteins, nucleic acids and lipids. Cancer cells are able to satisfy at least part of their demand for lipids through anabolic metabolism of nutrient-derived carbon. We have shown that lipid metabolism is important under the unfavourable conditions encountered in the tumour microenvironment, uncovering several metabolic genes that are essential in cancer, including SREBPs, FABPs, ACSS2 and SCD. More recently, utilizing our 3D functional genomics pipeline we have identified recurrently altered novel tumour suppressors, whose loss results in a fundamental rewiring of cancer metabolism. Together, this gives us a number of biomarkers and tractable nodes to target in cancer, with which we can assess the intrinsic and extrinsic factors that drive tumour biology and disease progression.

To investigate these dependencies we utilise functional genomics (RNAi), genetic perturbation modalities (CRISPR/Cas9) and small molecule inhibitors in combination with cell culture techniques that are more similar to the unfavourable tumour microenvironment encountered in vivo (cancer cell line spheroids).

Current projects:

• Elucidating the impact of a high fat diet on the development of cancers and whether inhibition of lipogensis is a tractable pathway in these tumours.
• Understanding the impact tumour suppressor loss has on metabolic alterations and whether nutrient supply influences disease trajectory

Other Activities

• Member of the British Association for Cancer Research
• Member of the European Association for Cancer Research

Major Funding

• 2019-2022 - Barts Charity, Understanding the role of cancer metabolism at the nexus of diet and tumour microenvironment
• 2023-2029, Cancer Research UK (CRUK) Career Establishment Award, 'Understanding and exploiting Acetyl-CoA metabolism in Small Cell Lung Cancer', ~£1.1M

Recent Publications

Abstract B020: SF3B1  hotspot mutations confer sensitivity to PARP inhibition through a defective replication stress response Bland P, Saville H, Wai PT et al. Molecular Cancer Therapeutics (2023) 22(10) b020-b020

SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response Bland P, Saville H, Wai PT et al. Nature Genetics (2023) 55(10) 1311-1323

TGFβ-mediated MMP13 secretion drives myoepithelial cell dependent breast cancer progression Gibson SV, Tomas Bort E, Rodríguez-Fernández L et al. npj Breast Cancer 9(10) 9

Abstract P6-10-05: Mutations in the RNA Splicing Factor SF3B1 drive endocrine therapy resistance and confer a targetable replication stress response defect through PARP inhibition Bland P, Saville H, Read A et al. Cancer Research (2023) 83(10) p6-10-05-p6-10-05

Inhibition of Stearoyl-CoA Desaturase Has Anti-Leukemic Properties in Acute Myeloid Leukemia Dembitz V, Lawson H, Philippe C et al. Blood (2022) 140(10) 3058-3060

Adipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence Heydt Q, Xintaropoulou C, Clear A et al. Nature Communications (2021) (1)

3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer Peck B, Bland P, Mavrommati I et al. Cancer Research (2021) 81(10) 847-859

A micronutrient with major effects on cancer cell viability Kapara A, Vannini A, Peck B Nature Metabolism (2020) (1)

Lipid Metabolism at the Nexus of Diet and Tumor Microenvironment Peck B, Schulze A Trends in Cancer (2019) 5(10) 693-703

3D Growth of Cancer Cells Elicits Sensitivity to Kinase Inhibitors but Not Lipid Metabolism Modifiers. Jones DT, Valli A, Haider S et al. Molecular Cancer Therapeutics (2019) 18(1) 376-388
https://www.ncbi.nlm.nih.gov/pubmed/30478149

Team

• Fabrizio Fai
• Lakshmi Rajput
• Lili Dimitrova

• Priyankush Choudhury

• James Boncan

Biography

I studied Molecular Biology and Genetics at Royal Holloway (University of London) before moving to Imperial College London to complete a PhD in the role and regulation of forkhead transcription factors in breast cancer. In 2010 I moved to the London Research Institute (now the Crick Institute) to the lab of Prof. Almut Schulze to study cancer metabolism. This work focussed on identifying novel cancer-specific dependencies in cancer metabolism. As part of the Lipid metabolism consortium, we identified ACSS2 and SCD as fundamental dependencies of aggressive breast and prostate cancers.

In 2014 I moved to the lab of Dr. Rachael Natrajan identifying novel tumour suppressors in breast cancer. At the ICR we developed bespoke 3-dimensional (3D) screening pipelines and discovered novel genes, including CREBBP, KMT2C and NIPBL that impact disease progression and response to targeted therapies.