Marcus Ruscetti Lab

Thanks again for the invite! Had a blast and learned a ton. The future of senescence research is bright.

With her NIH F31 fellowship, Kat Murphy is now leveraging these models to explore the molecular and cellular determinants of immune suppression and immunotherapy failure in another aggressive and highly metastatic form of CRPC: neuroendocrine prostate cancer. Stay tuned for more to come!

Thanks to editor @harmonyturk.bsky.social at Cancer Research, who made the publishing process streamlined and timely, and to our Reviewers, who provided helpful comments and suggestions that improved the manuscript.

Given the number of bispecific antibodies targeting VEGFR2/PD-L1 currently on the market and in clinical trials, we believe that the 8-9% of CRPC patients harboring MYC and p53 genetic alterations could highly benefit from these immunotherapies as a “precision medicine” approach.

Moreover, VEGFR2 blockade could potentiate anti-PD-L1 immune checkpoint blockade therapy that is generally ineffective in the broader prostate cancer patient population in our MYC and p53 altered CRPC models.

Treatment with VEGFR2 blocking antibodies could reactivate cytotoxic anti-tumor T cell immunity to block prostate tumor growth and metastasis in this aggressive MYC and p53-driven genetic CRPC subtype.

Mechanistically, MYC and p53 alterations cooperated to drive secretion of VEGF from prostate tumor cells. Though VEGF typically mediates vascular remodeling and angiogenesis, Kat found that VEGF could also directly reduce migration and activation of CD8+ T cells expressing its receptor, VEGFR2.

She identified a genetic subtype of castration-resistant prostate cancer (CRPC) with MYC oncogene overexpression and p53 tumor suppressor deletion that had reduced NK and T cell infiltration and activity compared to other subtypes and an overall dismal prognosis in mice and men.

Using an in vivo electroporation technique that allows for generation of any genetic alteration found in human cancers in mice, Kat produced a suite of prostate cancer mouse models with different oncogene and tumor suppressor alterations and analyzed their immune landscapes.

What are the genetic determinants of immune suppression and immunotherapy resistance in cancer? In a recent study from our lab, Kat Murphy developed innovative genetically engineered mouse models of late-stage prostate cancer to address this question.
aacrjournals.org/cancerres/ar...

Could not be more proud of Kat and all she has accomplished in graduate school and beyond!

Be sure to also check out her recent paper in Cancer Research elucidating genetic mechanisms of immune suppression and immunotherapy resistance in prostate cancer.

aacrjournals.org/cancerres/ar...

The fabulous Lin Zhou, the 1st author who drove the study, is currently on the job market. She is following up on this work to investigate how p21+ stromal cells arise, how they are different from other senescent cells, and how to best target them in cancer. Snatch her up before someone else does!

As always, it was a real pleasure working with Michele Hartsough and the editorial team at Cancer Discovery. And thanks to our Reviewers for their helpful comments along the way that improved the manuscript.

This was a great team effort from all authors, including my former Ph.D. mentor!

Our findings suggest that, in contrast to senescent transformed epithelial cells that are growth arrested and tumor suppressive, p21+ senescent stromal cells secrete a SASP that fuels immune suppression and tumor growth that can be targeted for therapeutic intervention and to enhance immunotherapy.

Targeting p21+ senescent stromal cells genetically or through treatment with ABT-263 could also enhance anti-PD-1 immune checkpoint blockade therapy outcomes in advanced, castration-resistant prostate cancer models.

Administration of the senolytic BCL-2 family inhibitor ABT-263 also preferentially targeted p21+ senescent stromal cells, leading to reactivation of anti-tumor T cell immunity that could even block prostate tumor initiation.

Through a series of experiments to deplete p16+ or p21+ senescent cells in different cellular compartments in mice, we found that while p16 removal had no effect on tumor progression, p21+ stromal cell depletion could block SASP to reverse myeloid immune suppression and delay tumor growth.

Whereas p16+ senescent epithelial cells had very low expression of inflammatory factors through the senescence-associated secretory phenotype (SASP), p21+ senescent stromal cells had high production of SASP cytokines that recruit suppressive myeloid cells.

To our surprise, single cell sequencing revealed that different populations of senescent cells expressed different senescent markers. While transformed senescent epithelial preferentially expressed p16, senescent cells in stromal populations expressed another putative senescence marker: p21.

Using patient samples and mouse models of early prostate cancer development, we found that senescent cells accumulate in both the tumor and the surrounding non-tumor stroma throughout disease progression, where they were associated with T cell suppression.

How can senescent cells, which are damaged and growth arrested, both block tumor initiation as well as fuel its growth? A recent study published in Cancer Discovery @aacrjournals.bsky.social from Lin Zhou in the lab uncovered some new insights into this puzzle.
aacrjournals.org/cancerdiscov...

Now online in Cancer Discovery @aacrjournals.bsky.social: p21-Positive Senescent Stromal Cells Promote Prostate Cancer Immune Suppression & Progression that Can Be Reversed by Senolytic Therapy - by Lin Zhou, @marcus-ruscetti.bsky.social, and colleagues doi.org/10.1158/2159... @umasschan.bsky.social

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.