Marcus Ruscetti Lab

Congrats to postdoc @nikitab.bsky.social for being awarded an AACR Scholar-in-Training award for this year's #AACRPan25 conference.

Be sure to check out her poster # B049 today from 6-9pm!

Forgot to tag @fitzgeraldkate.bsky.social! Great collaborating with you on this.

This was a team effort from members of our lab and a number of labs and colleagues with different expertise! Also very appreciative of the great feedback from our reviewers and assistance from editors and staff @pnas.org

Our study contributes a more generalizable approach to stabilize STING and increase immunogenicity in cold tumors where STING expression is silenced through targeting PPT1. We believe this could open the door for rationale combinations with STING agonists and ICB therapies.

Remarkably, analysis of patient datasets demonstrated that high PPT1 expression was associated with drastically reduced survival outcomes in cancer patients treated with immune checkpoint blockade therapies.

Use of a PPT1 small molecule inhibitor in clinical development could induce STING expression in tumor cells in vivo, leading to reduced tumor growth and activating CD8+T cells in mouse models of prostate and ovarian cancers.

Genetic or pharmacological inhibition of PPT1 could enhance STING protein expression and downstream signaling in tumor cells to induce production of cytokines important for anti-tumor immunity.

Mechanistically, she found the PPT1 promoted the turnover and lysosomal degradation of STING, leading to attenuation of its downstream inflammatory signaling capacity that can drive immune responses in cancer.

Shreya pulled out a number of negative regulators of STING expression from the screen, and focused on the palmitoyl-protein thioesterase PPT1, which she found to be overexpressed and amplified in human prostate and ovarian cancers with low STING levels.

This project initially began in the lab of the late great Michael R. Green, with the idea of performing a CRISPR screen to identify novel, targetable regulators of STING in tumor cells that often silence STING expression and as such are not responsive to STING agonists.

*NEW paper alert* In a recent study from our former postdoc Shreya Chowdhury and in collaboration with Kate Fitzgerald, we identified PPT1 as a negative regulator of STING in tumor cells whose targeting could reactivate T cell immunity in ovarian and prostate cancers.

www.pnas.org/doi/10.1073/...

Basal cell of origin resolves neuroendocrine–tuft lineage plasticity in cancer Nature - Basal cells, rather than neuroendocrine cells, have been identified as the probable origin of small cell lung cancer and other neuroendocrine–tuft cancers, explaining...

Super pleased to announce our latest suggesting the cell of origin for #SCLC is most likely the basal cell @nature.com, not the accepted neuroendocrine cell. Implications for the earliest events in cancer, & providing new models of tuft-like cancer.
rdcu.be/eGUtj

This month our lab is celebrating 5 years! Couldn't be more thrilled with and proud of the group we have. Great scientists and human beings all around. Also super excited about the science coming out of the lab. Stay tuned for a few new studies dropping in the upcoming weeks.

Congrats @nikitab.bsky.social !

Read the Letter Researchers at academic institutions nationwide say that U.S. science is being dismantled.

www.nytimes.com/interactive/...

Why do we even have to do this? I wondered the whole time at Stand for Science. 🧪 But it was inspiring to see so many people committed to fighting for truth, science, and justice!

#standupforscience Boston

Congrats to Haruka from the Atukorale and Ruscetti labs for passing her qualifying exam to become a Ph.D. candidate yesterday! We are proud mentors and can't wait to see what you can accomplish through engineering LNPs for drug delivery in pancreatic cancer!

Identifying specific functional roles for senescence across cell types A dual recombinase-mediated genetic system for cell-type-specific lineage tracing, ablation, and gene manipulation of senescent cells reveals distinct roles of senescence across cell types.

Original article here:

www.cell.com/cell/fulltex...

Lineage tracing senescence in vivo shows not all senescent cells are created equal Understanding the impact of senescence on disease is limited by the lack of tools to lineage label senescent cells. In a recent Cell issue, Zhao et al. create mouse models to genetically manipulate and trace p16+ cells, identifying contrasting roles for senescent macrophages and endothelial cells (ECs) in liver fibrosis.

Happy to highlight work from Zhao et al., who developed 4! new mouse models to trace and genetically manipulate different p16+ senescent cell types that will be invaluable to the field. Check out my spotlight @Dev_Cell and original article in @cellcellpress.bsky.social
www.cell.com/developmenta...

Cellular senescence offers distinct immunological vulnerabilities in cancer Chronic damage following oncogene induction or cancer therapy can produce cellular senescence. Senescent cells not only exit the cell cycle but communicate damage signals to their environment that can trigger immune responses. Recent work has revealed that senescent tumor cells are highly immunogenic, leading to new ways to activate antitumor immunosurveillance and potentiate T cell-directed immunotherapies. However, other studies have determined that heterogeneous senescent stromal cell populations contribute to immunosuppression and tumor progression, sparking the development of senotherapeutics to target senescent cells that evade immune detection. We review current findings that provide deeper insights into the mechanisms contributing to the dichotomous role of senescence in immune modulation and how that can be leveraged for cancer immunotherapy.

Happy to share our recent review on cellular senescence and its impact on tumor immune surveillance authored by Lin Zhou and Boyang Ma in the lab, out now online at Trends in Cancer. Lots of exciting developments in the field over the past few years worth checking out!
www.cell.com/trends/cance...

Lab Holiday party

Always wonderful to see how our lab family grows each year. Happy Holidays from the Ruscetti and @pitarresilab.bsky.social groups!

Engineered extrachromosomal oncogene amplifications promote tumorigenesis - Nature Large extrachromosomal DNAs are engineered using a CRISPR- and Cre–loxP-based approach and shown to drive cancer in mouse models, with potential applications in determining the role of oncogene a...

🧪1/ 🚨New paper on ecDNAs from our lab!
We reveal a strategy to engineer extrachromosomal DNA (ecDNA) amplifications in cells & mice. Let's dive in! Let’s dive in! 🧵👇
www.nature.com/articles/s41...

Ruscetti lab group photo September 2024

First post on @bsky.app! Excited to engage with the scientific community, share our lab's research on tumor immunology and cellular senescence, and highlight the work and accomplishments of our inspiring lab members on this platform.

Cell polarity proteins promote macropinocytosis in response to metabolic stress - Nature Communications Cancer cells rely on macropinocytosis to survive in a nutrient-deprived environment. Here, Lambies et al. identified various members of the cell polarity protein network as essential regulators of mac...

I'm thrilled to share our latest research, published in Nature Communications. This work highlights how pancreatic cancer cells hijack cell polarity proteins to regulate macropinocytosis and tumor metabolism, shedding light on potential therapeutic vulnerabilities.
www.nature.com/articles/s41...

No better 1st post on this platform than this - the Pitarresi and Ruscetti labs at UMass Chan raising awareness on World Pancreas Cancer Day. Surely a long way to go but fueled by a singular purpose of defeating this deadly malignancy!