Oliver Florey

Research Summary

Research in our lab is focused on the related topics of autophagy (self eating), macroendocytosis (digestion of extracellular material) and entosis (a recently discovered form of cell cannibalism). These are 3 distinct but inter-related forms of cellular ‘eating’, which play an important role in normal biology and become deregulated during ageing or disease (eg cancer).

Our work exploits a combination of molecular and cellular biology, state-of-the-art microscopy (long-term timelapse imaging, spinning disk confocal and electron microscopy) and proteomics (mass spectrometry).

Existing projects aim to define the molecular mechanisms which underlie cellular eating, with a particular focus on the emerging pathway of non-canonical autophagy. We are also investigating the intriguing relationship between entosis and cancer.

Latest Publications

CDK1, the Other 'Master Regulator' of Autophagy.
Odle RI, Florey O, Ktistakis NT, Cook SJ

Autophagy and cap-dependent mRNA translation are tightly regulated by the mechanistic target of rapamycin complex 1 (mTORC1) signalling complex in response to nutrient availability. However, the regulation of these processes, and mTORC1 itself, is different during mitosis, and this has remained an area of significant controversy; for example, studies have argued that autophagy is either repressed or highly active during mitosis. Recent studies have shown that autophagy initiation is repressed, and cap-dependent mRNA translation is maintained during mitosis despite mTORC1 activity being repressed. This is achieved in large part by a switch from mTORC1- to cyclin-dependent kinase 1 (CDK1)-mediated regulation. Here, we review the history and recent advances and seek to present a unifying model to inform the future study of autophagy and mTORC1 during mitosis.

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Trends in cell biology, 1, 1, 30 Nov 2020

PMID: 33272830

An mTORC1-to-CDK1 Switch Maintains Autophagy Suppression during Mitosis.
Odle RI, Walker SA, Oxley D, Kidger AM, Balmanno K, Gilley R, Okkenhaug H, Florey O, Ktistakis NT, Cook SJ

Since nuclear envelope breakdown occurs during mitosis in metazoan cells, it has been proposed that macroautophagy must be inhibited to maintain genome integrity. However, repression of macroautophagy during mitosis remains controversial and mechanistic detail limited to the suggestion that CDK1 phosphorylates VPS34. Here, we show that initiation of macroautophagy, measured by the translocation of the ULK complex to autophagic puncta, is repressed during mitosis, even when mTORC1 is inhibited. Indeed, mTORC1 is inactive during mitosis, reflecting its failure to localize to lysosomes due to CDK1-dependent RAPTOR phosphorylation. While mTORC1 normally represses autophagy via phosphorylation of ULK1, ATG13, ATG14, and TFEB, we show that the mitotic phosphorylation of these autophagy regulators, including at known repressive sites, is dependent on CDK1 but independent of mTOR. Thus, CDK1 substitutes for inhibited mTORC1 as the master regulator of macroautophagy during mitosis, uncoupling autophagy regulation from nutrient status to ensure repression of macroautophagy during mitosis.

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Molecular cell, S1097-2765, 19, 06 Nov 2019

DOI: 10.1016/j.molcel.2019.10.016

PMID: 31733992

Macropinocytosis and autophagy crosstalk in nutrient scavenging.
Florey O, Overholtzer M

Adaptive strategies used by cells to scavenge and recycle essential nutrients are important for survival in nutrient-depleted environments such as cancer tissues. Autophagy and macropinocytosis are two major mechanisms that promote nutrient recycling and scavenging, which share considerable, yet poorly understood, cross-regulation. Here we review recent findings that connect these starvation response mechanisms and discuss the implications of their crosstalk. This article is part of the Theo Murphy meeting issue 'Macropinocytosis'.

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Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 374, 1471-2970, 2019

PMID: 30967004

entosis and the formation of a cell-in-cell structure by MCF10A cells
A) Sequence of images showing entosis and the formation of a cell-in-cell structure by MCF10A cells in suspension. Cell 1 is engulfed by Cell 2.

B) H&E staining from a human breast carcinoma, arrows point to cell-in-cell structures (taken from Biomax.us).

C) Immunofluorescent staining of b-catenin in a cell-in-cell structure from a human breast tumor.

D) Immunofluorescent staining of E-cadherin in a cell-in-cell structure from MCF10A cells.