A 60 second video clip of Episode 5 in which we chronicle the fascinating story behind Continuous Glucose Monitors (CGMs) and of Adam Heller the man who built technologies that advanced these devices.

Finally, TAK-981 robustly suppressed tumor growth in xenograft models, reducing tumor growth, decreasing SS18::SSX protein levels, and lower cellularity. This study strongly indicates SUMO2 inhibition as an effective therapeutic strategy against synovial sarcoma in vivo.

Prior studies (McBride et al., Benabdallah N. et al., Boulay G. et al.,) have demonstrated H2AK119ub activation by SS18::SSX fusions. We observed that SUMO2 inhibition substantially reduced H2AK119ub, esp. at fusion target sites corresponding with fusion loss.

These results were borne out by CUT&Tag which showed strongly diminished SS18::SSX fusion protein on chromatin after SUMO2 inhibition using TAK-981.

Surprisingly, SUMO2 inhibition did not just reverse downstream targets, but also SS18::SSX protein levels themselves. Both shRNA and TAK-981 treatments lowered fusion protein levels across different variants (SSX1 and SSX2), establishing SUMO2 as a regulator of the fusion itself.

Fusion activated oncogenic targets (e.g., HOXA10, SUZ12, TYMS) were down-regulated, while fusion-repressed genes such (e.g., KLF4, GADD45B) were derepressed upon SUMO2 inhibition.

Surprisingly, transcriptomic studies revealed that SUMO2 inhibition showed a dramatic reversal of the transcriptional program of SS18::SSX fusions described in Jerby-Arnon L, et al. (Regev Lab).

Genetic knockdown of SUMO2 had similar effects

We were also excited about SUMO2 because of the availability of TAK-981, a potent, clinical-stage SUMO2 inhibitor which strongly suppressed growth of synovial sarcoma lines, increased apoptosis, and dramatically reduced colony-forming ability of synovial sarcoma cells at low nM

We then conducted targeted CRISPR screens in vitro and in vivo using synovial sarcoma cells, and SUMO2 emerged as one of the strongest dependencies in both - validating DepMap predictions. Since SUMO2 was also a SS18::SSX fusion target, was prioritized for further studies.

So, we began with the dependency maps dataset (DepMap) to ask: which genes are selectively essential for synovial sarcoma compared to other cancers?

In addition to expected genes (SS18, SSX, BRD9), one pathway jumped out: SUMOylation. And right at the core of this was SUMO2.

A few years ago, we got interested in Synovial Sarcoma - an aggressive, difficult-to-treat cancer. There is a single fusion protein - the SS18::SSX fusion - that drives this malignancy, but there isn’t much known about actionable vulnerabilities in this disease.

Really excited that our manuscript on Synovial Sarcoma is now online. Link to Open Access PDF: tinyurl.com/55bnssws

A summary🧵 :

Always a bittersweet moment when a PhD student from the lab graduates.Terrific work and what a thesis defense talk Rema Iyer ! Congratulations on your degree!

Maybe a bit passive aggressive this messaging from me. Should tone it down?

Today, the lab turned 10 years old. After a shaky beginning, we embarked on some really fun projects, made discoveries, and trained extraordinary people. I am particularly excited by upcoming studies in our lab, and it looks like the fun has just begun. Looking forward to the next 10 and more.

Fabulous Deshpande/Adams/Bagchi/Dhar joint lab holiday trip to the Anza Borrego desert near San Diego. Those who are traveling to #ASH24 this week can expect this winter weather!

Our institute is excited to host The Myeloid Precursor this Thursday, a fun mini symposium on AML with great talks, a panel discussion on AML therapeutics, and a poster session. If you are in San Diego this Thursday and interested, please register here. forms.office.com/r/Sq59VV1vh7