Carroll Group

Research summary

Our group studies how certain cancers grow and spread, especially those that depend on hormones. We focus on special proteins called transcription factors, which control genes by turning them on and off. These genes can tell cancer cells to keep growing. We want to find where these control points are and how these proteins interact with them so we can find ways to stop cancer growth.

Introduction

We are interested in defining the genomic and molecular features of transcription factors in cancer. We are specifically focused on identifying, characterising and modulating pioneer factors, a specialised class of transcription factors that create regulatory elements and initiate gene expression events. Pioneer factors are important in defining cell lineage and phenotype making them critical in cancer development and progression. The archetypal pioneer factor is a protein called FOXA1, which plays a critical role in the most common breast cancer subtype, Estrogen Receptor positive (ER+) breast cancer, as well as in prostate cancer. More recently, FOXA1 has been shown to play a role in other cancer types, including pancreatic cancer.

FOXA1 and other pioneer factors are able to open compacted chromatin, creating enhancer elements that can subsequently be used by nuclear receptor transcription factors, such as Estrogen Receptor in breast cancer and Androgen Receptor in prostate cancer. These nuclear receptors can then form the platform for recruitment of co-factors, many of which have enzymatic or structural roles required for the regulation of transcription.

We are interested in understanding how these nuclear receptors interact with the DNA, what the critical functional co-factors are and how changes in pioneer factor levels or fidelity can alter these processes. A major part of this is identifying where in the genome the transcription factors associate with the DNA and what the proteins are in the complexes at these binding sites. We use various genomic approaches and couple these with proteomic approaches to characterise these events. A method we developed called RIME (and the quantitative version called qPLEX-RIME) permits the discovery of protein complexes and is one of the only approaches for protein interactome discovery that is applicable for clinical tissue. The RIME approach enables the discovery of important protein complexes in tumour tissue, as well as being a fantastic tool for identifying how key protein complexes change from treatment sensitive to treatment resistant cancers, and from primary tumours to metastases.

Professor Jason Carroll

Senior Group Leader
Associate Director of Research Culture and Innovation

Carroll Group external website

Biography

Jason is an Australian who completed a PhD in 2002 at the University of New South Wales and the Garvan Institute, Sydney, with Prof Robert Sutherland. He conducted postdoctoral work with Prof. Myles Brown at Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA from 2002-2006. He has been running his own group at Cancer Research UK, Cambridge Institute and University of Cambridge since 2007. He is currently a Professor of Molecular Oncology at the University of Cambridge, a Senior Group Leader at Cancer Research UK, a Fellow at Clare College and was elected an EMBO member in 2016 and a Fellow of the Academy of Medical Sciences in 2017. He is the academic head of the breast cancer program in Cambridge. His lab is interested in understanding mechanisms of hormone-dependent cancer.

Professor Jason Carroll

Senior Group Leader
Associate Director of Research Culture and Innovation

Visit the Carroll Group’s external site

Company	Active	Research funding	Ownership	Royalty payments	Commitment to cary out work for a fee	Ad hoc reimbursed work	Travel	Gifts/other
Azeria Therapeutics	No	No	Yes	No	Yes	No	No	No
Genentech	No	Yes	No	No	Yes	No	No	No
AstraZeneca	No	Yes	No	No	Yes	No	No	Yes
Seragon	No	Yes	No	No	Yes	No	No	No
Active Motif	No	No	No	Yes	No	No	No	No
Nature Publishing Group	Yes	No	No	No	Yes	No	No	No
AACR Journals	Yes	No	No	No	Yes	No	No	No

Research topics

Identifying the proteins and perturbations that drive disease progression

We focus on characterising the events that culminate in ER-mediated gene expression. This involves mapping ER and co-factor binding sites from models and tumour tissue and defining the genomic properties that enable ER to mediate gene expression from distal enhancer elements. We have been particularly focused on mapping transcription factor binding sites from clinical tissue and we were one of the first labs to establish transcription factor mapping from tumour samples. We are specifically interested in identifying the key co-factors in ER+ breast cancer, with the goal of using small molecule inhibitors against these proteins, based on novel biological insight. We identify the genomic changes that can contribute to disease progression, including the identification of genes and proteins that mediate treatment resistance and metastasis. We use many approaches to define these events, including CRISPR screens, proteomics and genomics, which we integrate with data from clinical samples to inform us on candidates that are likely to be functionally important. We do deep functional characterisation of how identified molecular changes contribute to resistance and metastasis, in part by exploiting the physiologically-relevant intraductal system that, for the first time, accurately models ER+ breast cancer metastasis.

In addition to understanding how ER functions in ER+ breast cancer, we explore the substantial cross-talk that exists between ER and other nuclear receptors in breast cancer. Work from our group and our collaborators have shown that Progesterone Receptor and Androgen Receptor, both have the ability to impinge on ER activity by competing with ER for both DNA binding sites and rate-limiting co-factors. We use this information to inform clinical trials that exploit PR and AR ligands for therapeutic use in ER+ breast cancer patients.

Defining how FOXA1 functions and discovering novel pioneer factors

FOXA1 is the archetypal pioneer factor, where it can bind to compacted chromatin, opening that region of the DNA and subsequently recruiting the COMPASS complex, that initiate the events that ultimately create de novo enhancer elements. As such, FOXA1 is the first step in the creation of enhancers in the contexts where it is expressed, which includes ER+ breast and prostate cancer. Although we know that FOXA1 is an essential gene in these cancers and a biomarker of these tumours, we still do not completely understand how FOXA1 functions and what happens when FOXA1 is altered. This is particularly important given that perturbations in FOXA1 expression and fidelity are commonly observed in advanced disease.

We are interested in defining how FOXA1 associates with the DNA, what proteins are essential for it to function and whether there are post-translational modifications on FOXA1 that alter its activity and might be therapeutically exploited. We take unbiased screening approaches to understand what regulates FOXA1 expression and protein stability and what allows it to mediate COMPASS complex recruitment and therefore enhancer creation. We are identifying amino acid residues on FOXA1 that are important for its ability to be a pioneer factor as well as looking for similarities and differences between its mechanism of action in breast and prostate cancer.

A parallel part of the group is interested in developing new methodological approaches for discovering novel pioneer factors in cancer types where these are not well characterised.

Defining the transcriptional mechanisms in prostate and pancreatic cancer

In prostate cancer, FOXA1 is also a pioneer factor, but in this context is recruits Androgen Receptor (AR). We are interested in defining how FOXA1 and AR co-operate, but our main focus is defining advanced prostate cancer, specifically neuroendocrine prostate cancer (NEPC). NEPC is an aggressive subtype of prostate cancer that we know little about, but it has increased in frequency, in response to more potent tAR-targeted treatments. We are specifically interested in defining the role of FOXA1 in NEPC, as well as discovering NEPC-specific transcription factors and co-factors that are important for this aggressive and difficult to treat cancer subtype.

Recent evidence has suggested that FOXA1 becomes co-opted in pancreatic adenocarcinoma (PDAC), where is creates new enhancer elements that are associated with PDAC metastasis. We focus on characterising the role of FOXA1 in PDAC, with the goal of identifying where it plays a role and how it makes these transcriptional events occur. We are focused on identifying the proteins that FOXA1 works with, in order to identify therapeutic vulnerabilities that we can exploit for pancreatic cancer patients.