Harnessing Cellular Senescence for Cancer Immunotherapy

Presented virtually during the New Faculty Talks session at the 25th Annual University of Massachusetts Medical School Research Retreat 2020 on October 26, 2020

The Role of the Tumor Microenvironment and Epithelial-Mesenchymal Plasticity in Prostate Cancer Progression and Metastasis

PTEN is one of the most commonly deleted tumor suppressor genes in human prostate cancer. Our group previously demonstrated that Pten deletion in the murine prostate epithelium recapitulates the disease progression seen in human prostate cancer, culminating in invasive adenocarcinoma. In addition to Pten loss endowing prostate cells with enhanced proliferative capacity, we found that Pten loss also led to the upregulation of inflammatory pathways, including Csf-1 and Il1b expression, within the prostate epithelium. These inflammatory cytokines recruit myeloid-derived suppressor cells (MDSCs) into the prostate, which subsequently promote an immune-suppressive tumor microenvironment and thereby facilitate tumor progression. Targeting immune-responsive pathways with the CSF-1R inhibitor GW2580 successfully inhibits MDSC infiltration and delays tumor progression. As Pten deletion alone does not produce distant macrometastasis, we surveyed additional pathways altered in human metastatic prostate cancer, and found that the RAS/MAPK pathway was significantly elevated in metastatic lesions. Indeed, when we combined Pten deletion with Kras activation in the prostate epithelium (Pb-Cre+/-;PtenL/L;KrasG12D/+) (CPK), we observed macrometastasis to the lungs and liver. Interestingly, within the prostate, we observed an epithelial-mesenchymal transition (EMT) phenotype, accompanied by significant upregulation of the EMT transcription factor Snail. Importantly, genetic deletion of Snail in CPK mice prevented distant macrometastasis, providing a mechanistic link between EMT and metastasis.To study the dynamic regulation of the EMT process, we crossed CPK mice with Vimentin-GFP reporter mice (CPKV), and were able to isolate populations of epithelial, EMT, and mesenchymal-like prostate tumor cells. We demonstrate that EMT and mesenchymal-like tumor cells have enhanced stem-like and tumor-initiating capacities and exhibit cellular plasticity in vivo. HMGA2, a chromatin remodeling protein, is significantly upregulated in EMT and mesenchymal-like tumor cells, as well as in human metastatic castration-resistant prostate cancer (mCRPC). Knockdown of Hmga2, or suppressing Hmga2 expression with the HDAC inhibitor LBH589, inhibits epithelial-mesenchymal plasticity and stemness activities in vitro and dramatically reduces prostate tumor burden and distant metastasis in vivo. Importantly, LBH589 in combination with castration significantly prolongs survival by targeting castration-resistant mesenchymal-like tumor cells and preventing mCRPC. LBH589 treatment in combination with androgen deprivation therapy may therefore be a promising treatment for patients with mCRPC

New Faculty Talks

Moderator: Dr. Roger Davis, Chair and Professor in Molecular Medicine Presenters: Dr. TengTing (Elaine) Lim, Assistant Professor, Program in Bioinformatics and Integrative Biology and Molecular, Cell and Cancer Biology: “Multiplexing and demultiplexing with cerebral organoids for neurological diseases” Dr. William Flavahan, Assistant Professor, Molecular, Cell and Cancer Biology: “Insulator dysfunction and epigenetic alterations as tumor drivers Dr. Marcus Ruscetti, Assistant Professor, Molecular, Cell and Cancer Biology: Harnessing cellular senescence for cancer immunotherapy

Adenocarcinoma of the Prostate: Future Directions for Translational Science

Adenocarcinoma of the prostate is a common malignancy affecting one in nine men, with six of every 10 cases identified in men older than 66 years, and more adversely affects African American males. It remains less common in men under the age of 40. The age adjusted incidence is increasing with the application of prostate specific antigen (PSA) as a biomarker. PSA helps identifying the disease at an early stage, which is treatable and curable with traditional therapies. However, a significant percentage of men present with high Gleason grade and advanced disease, with lower PSA, and younger age at presentation. These patients can have a compromised outcome. Once again, we are evaluating patients under the age of 50 with advanced disease due in part to inconsistent application of clinical screening. More effort is needed for high-risk patients to provide timely, meaningful intervention and effective therapy. In this chapter, we review the status of therapy for standard and high-risk patients, and strategies for translational science for patients at risk of compromised outcome and treatment failure

Pten Null Prostate Epithelium Promotes Localized Myeloid-Derived Suppressor Cell Expansion and Immune Suppression during Tumor Initiation and Progression

Chronic inflammation is known to be associated with prostate cancer development, but how epithelium-associated cancer-initiating events cross talk to inflammatory cells during prostate cancer initiation and progression is largely unknown. Using the Pten null murine prostate cancer model, we show an expansion of Gr-1(+) CD11b(+) myeloid-derived suppressor cells (MDSCs) occurring intraprostatically immediately following epithelium-specific Pten deletion without expansion in hematopoietic tissues. This MDSC expansion is accompanied by sustained immune suppression. Prostatic Gr-1(+) CD11b(+) cells, but not those isolated from the spleen of the same tumor-bearing mice, suppress T cell proliferation and express high levels of Arginase 1 and iNOS. Mechanistically, the loss of PTEN in the epithelium leads to a significant upregulation of genes within the inflammatory response and cytokine-cytokine receptor interaction pathways, including Csf1 and Il1b, two genes known to induce MDSC expansion and immunosuppressive activities. Treatment of Pten null mice with the selective CSF-1 receptor inhibitor GW2580 decreases MDSC infiltration and relieves the associated immunosuppressive phenotype. Our study indicates that epithelium-associated tumor-initiating events trigger the secretion of inflammatory cytokines and promote localized MDSC expansion and immune suppression, thereby promoting tumor progression

Somatic Tissue Engineering in Mouse Models Reveals an Actionable Role for WNT Pathway Alterations in Prostate Cancer Metastasis.

To study genetic factors influencing the progression and therapeutic responses of advanced prostate cancer, we developed a fast and flexible system that introduces genetic alterations relevant to human disease directly into the prostate glands of mice using tissue electroporation. These electroporation-based genetically engineered mouse models (EPO-GEMM) recapitulate features of traditional germline models and, by modeling genetic factors linked to late-stage human disease, can produce tumors that are metastatic and castration-resistant. A subset of tumors with alterations acquired spontaneous WNT pathway alterations, which are also associated with metastatic prostate cancer in humans. Using the EPO-GEMM approach and an orthogonal organoid-based model, we show that WNT pathway activation drives metastatic disease that is sensitive to pharmacologic WNT pathway inhibition. Thus, by leveraging EPO-GEMMs, we reveal a functional role for WNT signaling in driving prostate cancer metastasis and validate the WNT pathway as therapeutic target in metastatic prostate cancer. SIGNIFICANCE: Our understanding of the factors driving metastatic prostate cancer is limited by the paucity of models of late-stage disease. Here, we develop EPO-GEMMs of prostate cancer and use them to identify and validate the WNT pathway as an actionable driver of aggressive metastatic disease.