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Posts by Gerry Brien

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📣 I'm excited to share our latest preprint!

We adapt and characterise a neurosphere-based CNCC differentiation protocol, and demonstrate utility for quantitative phenotyping and craniofacial disease modelling! 🧫

Read about Array-CNCC here:
www.biorxiv.org/content/10.6...

@uoe-igc.bsky.social

2 months ago 49 14 2 1

We're also super excited to point you towards a wonderful, highly complimentary study from our colleagues Ana Banito and @nsbenab.bsky.social

www.biorxiv.org/content/10.6...

2 months ago 4 2 0 0
SS18-SSX co-opts P300 to sustain oncogenic transcription independent of SWI/SNF activity Synovial sarcoma is driven by the SS18-SSX fusion oncoprotein, which has been assumed to promote tumorigenesis through its incorporation into the SWI/SNF chromatin remodeling complexes. Accordingly, therapeutic efforts have focused on targeting SS18-SSX containing SWI/SNF assemblies, yet these approaches have produced limited clinical benefit. Here, we demonstrate that SS18-SSX sustains oncogenic transcription independent of SWI/SNF activity. Despite efficient degradation and dismantling of SWI/SNF complexes, fusion occupancy at target loci and associated gene expression programs remain largely intact. Instead, we identify the acetyltransferase P300 as an essential co-factor supporting SS18-SSX chromatin binding and transcriptional activation. Targeting P300 displaces the fusion from chromatin, suppresses its transcriptional output, compromising synovial sarcoma viability. Notably, dual PROTAC mediated degradation of P300 and SWI/SNF produces strong synergistic effects, broadly disrupting SS18-SSX localization and function. These findings redefine the mechanistic basis of synovial sarcoma and reveal a mechanistically anchored therapeutic strategy for targeting its core oncogenic driver. ### Competing Interest Statement C.R.V. has been a consultant for Flare Therapeutics, Roivant Sciences and C4 Therapeutics; has served on the advisory boards of KSQ Therapeutics, Syros Pharmaceuticals and Treeline Biosciences; has received research funding from Boehringer Ingelheim and Treeline Biosciences; and owns stock in Treeline Biosciences. S.A.A. has been a consultant and/or shareholder for Neomorph, Imago Biosciences, Hyku Therapeutics, C4 Therapeutics, Accent Therapeutics and Nimbus Therapeutics; and has received research support from Janssen and Syndax. N.O.C. is a co-founder, shareholder and management consultant for PhenoTherapeutics Ltd; and a shareholder in Amplia Therapeutics Ltd All other authors declare no financial interests UKRI, EP/X039633/1 Worldwide Cancer Research, https://ror.org/031tfbz57, 21-0271 Science Foundation Ireland, https://ror.org/0271asj38, 18/SIRG/5573

Take home points:

📌 SS18-SSX drives transcription largely independent of SWI/SNF

📌 P300 is an essential co-factor for fusion protein binding and activity

📌 Dual p300 and SWI/SNF targeting offers a mechanistically grounded therapeutic strategy.

Preprint - www.biorxiv.org/content/10.6...

2 months ago 2 0 1 0

Combining degraders targeting p300 and SWI/SNF:

🧬 Strong synergy in SS18–SSX–positive cells

🧬 Profound loss of SS18–SSX chromatin binding

🧬 Broad collapse of oncogenic gene expression

🧬 Dramatic loss of cell viability

2 months ago 2 0 1 0

SWI/SNF and p300 impact different subsets of SS18-SSX binding sites

This gave us an idea...

👉 What if we therapeutically target both?

2 months ago 0 0 1 0

To recap:

Remove SWI/SNF ➡️ Modest effects on SS18-SSX binding

Remove p300 ➡️ Major loss of SS18-SSX occupancy and transcription

❗ P300, not SWI/SNF, sustains the oncogenic program

2 months ago 1 0 1 0

We found that p300 is physically and functionally coupled to SS18-SSX

🧬 Co-localises with SS18-SSX on chromatin

🧬 Supports SS18-SSX binding at target sites

🧬 Required for SS18-SSX driven transcription

➡️ Remove p300 and SS18-SSX falls of chromatin

2 months ago 1 0 1 0
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So, what is the engine?

️A focused CRISPR screen revealed a striking dependency on p300

🧬 Not its paralog CBP

🧬 Specific to SS18-SSX positive sarcoma lines

2 months ago 1 0 1 0

Even when SWI/SNF activity is broadly eliminated:

🧬 Oncogenic transcription does not shut down

🧬 SS18-SSX transcriptional activity persists

➡️ Conclusion: SWI/SNF is not the main engine of SS18-SSX driven transcription

2 months ago 2 0 1 0

We used degraders to dismantle SWI/SNF complexes entirely, including SS18-SSX containing assemblies.

Result:

🧬 SWI/SNF complexes collapse

🧬 SS18-SSX stays bound at many target loci

🧬 Gene expression stays largely intact

2 months ago 3 0 1 0

Clinical efforts to target SWI/SNF (e.g. BRD9 degraders, based on our previous discoveries) have shown limited and transient benefits in synovial sarcoma patients.

So, we asked a simple question:

👉 Does SS18-SSX actually need SWI/SNF to drive oncogenic transcription?

2 months ago 2 0 1 0
SS18-SSX co-opts P300 to sustain oncogenic transcription independent of SWI/SNF activity Synovial sarcoma is driven by the SS18-SSX fusion oncoprotein, which has been assumed to promote tumorigenesis through its incorporation into the SWI/SNF chromatin remodeling complexes. Accordingly, therapeutic efforts have focused on targeting SS18-SSX containing SWI/SNF assemblies, yet these approaches have produced limited clinical benefit. Here, we demonstrate that SS18-SSX sustains oncogenic transcription independent of SWI/SNF activity. Despite efficient degradation and dismantling of SWI/SNF complexes, fusion occupancy at target loci and associated gene expression programs remain largely intact. Instead, we identify the acetyltransferase P300 as an essential co-factor supporting SS18-SSX chromatin binding and transcriptional activation. Targeting P300 displaces the fusion from chromatin, suppresses its transcriptional output, compromising synovial sarcoma viability. Notably, dual PROTAC mediated degradation of P300 and SWI/SNF produces strong synergistic effects, broadly disrupting SS18-SSX localization and function. These findings redefine the mechanistic basis of synovial sarcoma and reveal a mechanistically anchored therapeutic strategy for targeting its core oncogenic driver. ### Competing Interest Statement C.R.V. has been a consultant for Flare Therapeutics, Roivant Sciences and C4 Therapeutics; has served on the advisory boards of KSQ Therapeutics, Syros Pharmaceuticals and Treeline Biosciences; has received research funding from Boehringer Ingelheim and Treeline Biosciences; and owns stock in Treeline Biosciences. S.A.A. has been a consultant and/or shareholder for Neomorph, Imago Biosciences, Hyku Therapeutics, C4 Therapeutics, Accent Therapeutics and Nimbus Therapeutics; and has received research support from Janssen and Syndax. N.O.C. is a co-founder, shareholder and management consultant for PhenoTherapeutics Ltd; and a shareholder in Amplia Therapeutics Ltd All other authors declare no financial interests UKRI, EP/X039633/1 Worldwide Cancer Research, https://ror.org/031tfbz57, 21-0271 Science Foundation Ireland, https://ror.org/0271asj38, 18/SIRG/5573

Synovial sarcoma is driven almost exclusively by a single oncofusion – SS18-SSX

For years, the assumptions on disease mechanisms were simple:

➡️ SS18-SSX works by hijacking SWI/SNF chromatin remodeling activity

Our new study shows that assumption was wrong 🧵👇

www.biorxiv.org/content/10.6...

2 months ago 30 12 2 3

Just a few days after international DMG/DIPG day, our paper showing the importance of CBX4/PCGF4 containing cPRC1 complexes in glioma is out in @cp-molcell.bsky.social. Below is a nice synopsis of the paper by joint first author @EimearLagan.bsky.social

11 months ago 8 1 0 0
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Excited to share our new paper out today in @cp-molcell.bsky.social! We show that the H3K27M oncohistone rewires cPRC1, creating a unique dependency on CBX4/PCGF4-containing complexes, and also reveal a previously unknown function of CBX4. Highlights below (1/11).

11 months ago 23 10 5 2
A specific form of cPRC1 containing CBX4 is co-opted to mediate oncogenic gene repression in diffuse midline glioma Lagan, Gannon, et al. reveal that H3K27M-DMGs depend on a specific form of cPRC1 containing CBX4 and PCGF4. H3K27M alters H3K27me3 distribution, causing increased binding of CBX4-PCGF4-cPRC1 and oncogenic gene repression. CBX4’s ability to read H3K27me3 and to form a specific cPRC1 complex with PCGF4 makes it essential in DMG.

Online Now: A specific form of cPRC1 containing CBX4 is co-opted to mediate oncogenic gene repression in diffuse midline glioma Online now:

11 months ago 6 5 0 0