Prostate Tumor Progression Research Articles

Prostate Cancer Progression Modeling Provides Insight into Dynamic Molecular Changes Associated with Progressive Disease States.

We developed and validated a progression model of prostate cancer using >1,000 tumor and normal tissue samples. The model provided a comprehensive view of prostate tumor evolution and progression.

Abstract 3845: High-intensity focused ultrasound ablation increases tumor specific lymphocytes in prostate cancer

Abstract The treatment of localized prostate cancer has been revolutionized by High-Intensity Focused Ultrasound (HIFU), an FDA-approved procedure. Thermal HIFU achieves the destruction of tumor tissue through the noninvasive delivery of ultrasonic energy, causing rapid heating of the targeted area. Given that prostate cancer typically exhibits a low presence of tumor-infiltrating lymphocytes crucial for antitumor immunity, this study aimed to investigate whether HIFU has the potential to activate antitumor immunity and enhance lymphocyte infiltration within the tumor. RM1 tumors were implanted on the flanks of syngeneic C57BL/6J mice, with one tumor subjected to HIFU treatment. The growth of the contralateral tumor was monitored, and at the end of the study, tumors were collected to evaluate immune cell infiltration. Blood samples were obtained from patients both before and after prostatectomy or HIFU treatment. Peripheral blood mononuclear cells (PBMCs) were then isolated to analyze the immune cell population. In murine experiments, the application of HIFU to one tumor resulted in a reduction in the growth of the contralateral (untreated) tumor, specifically when the contralateral tumor was of the same type, but not when it was a different tumor type. Notably, HIFU led to an augmented infiltration of CD4+ and CD8+ lymphocytes into the contralateral (untreated) tumor. Depletion studies further affirmed that the antitumor immune response triggered by HIFU relies on CD4+ and CD8+ lymphocytes. In human subjects, HIFU was observed to elevate the CD4+ and CD8+ lymphocyte populations in PBMCs. HIFU induces a potent antitumor immune response that effectively inhibits the progression of murine prostate tumors. This immune response is contingent upon CD4+ and CD8+ lymphocytes. HIFU demonstrates significant promise in activating antitumor immune responses in patients diagnosed with prostate cancer. Subsequent research endeavors should delve into models of metastatic prostate cancer, exploring the potential synergy of cytoreductive prostate tumor ablation with systemic immunotherapies to elicit a robust and comprehensive antitumor immune response. Citation Format: Shengchen Su, Yanping Wang, Eric M. Lo, Hyung L. Kim. High-intensity focused ultrasound ablation increases tumor specific lymphocytes in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3845.

Abstract 462: Developing the miR-888 cluster as a therapeutic target for prostate cancer

Abstract Prostate Cancer (PCa) is a serious health crisis in the United States. 20% of men diagnosed with PCa will progress to fast-growing, advanced disease. There are no curative treatment options for PCa that has spread to distant sites and the 5-year survival rate for metastatic disease remains 30%. Recognizing the need for better PCa therapeutics, we are developing novel anti-microRNA delivery reagents targeted against the noncoding RNA miR-888 cluster to block prostate tumor progression. Our lab identified these oncomiRs in a biomarker discovery screen as elevated in human metastatic PCa cell lines and prostatic fluids from patients with high-grade PCa. We noted that over-expression of miR-888 cluster members (miR-888, miR-891a) promoted prostate cell growth and induced invasiveness in vitro. miR-888 and miR-891a also accelerated xenograft tumor growth in mice. Treatment of aggressive PCa cells in culture with synthetic antisense inhibitors against individual cluster members reversed these growth and invasion phenotypes, highlighting their clinical potential. We are testing pH Low Insertion Peptide (pHLIP)-Peptide Nucleic Acid (PNA)-based antimiR conjugates against miR-888 and miR-891a. The delivery vehicle pHLIP is a 36-amino acid peptide that at low pH (< pH 6.5) adopts an alpha-helical conformational change and facilitates the insertion of its C-terminus across lipid bilayers to transport conjugated anti-miRNA cargo into cells. When administered systemically, pHLIP effectively targets solid tumors with acidic microenvironments. We found that these reagents are readily internalized by human PCa cells cultured at pH 6.0 and in prostate xenograft tumors when delivered systemically in mice. Treatment significantly repressed miR-888 and miR-891a and acted to slow prostate cell growth in vitro. We are currently moving these studies into mouse prostate models. Furthermore, we are investigating the downstream signaling pathways for the miR-888 cluster. Our work indicates that the miR-888 cluster network coordinates the repression of the Tissue Inhibitors of Metalloproteinase (TIMP) and SMAD4 anti-metastatic pathways to drive extracellular matrix degradation and prostate cell invasion, and as a consequence, induces matrix metalloproteinase (MMP) activity. Expression profiling arrays and luciferase reporter assays indicated that multiple members of the miR-888 cluster co-suppress TIMPs in the prostate and similarly elevate multiple MMPs as well as cadherins, fibronectin and heparinase, and co-modulated several immune response genes. We are currently studying the consequence of various CRISPR-mediated miR-888 cluster deletions to understand how this non-coding RNA cluster functionally overlaps to promote aggressive PCa. This work will establish new clinical tools for aggressive PCa and optimize patient treatment management. Citation Format: Katherine Routon, Trevor Fachko, Vishal Kasina, Raman Bahal, Aurora Esquela Kerscher. Developing the miR-888 cluster as a therapeutic target for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 462.

Retracted: Long Noncoding RNA SNHG12 Promotes Prostate Tumor Occurrence and Progression via AKT Regulation.

[This retracts the article DOI: 10.1155/2020/8812923.].

The potential role of the microbiota in prostate cancer pathogenesis and treatment.

The human body hosts a complex and dynamic population of trillions of microorganisms - the microbiota - which influences the body in homeostasis and disease, including cancer. Several epidemiological studies have associated specific urinary and gut microbial species with increased risk of prostate cancer; however, causal mechanistic data remain elusive. Studies have associated bacterial generation of genotoxins with the occurrence of TMPRSS2-ERG gene fusions, a common, early oncogenic event during prostate carcinogenesis. A subsequent study demonstrated the role of the gut microbiota in prostate cancer endocrine resistance, which occurs, at least partially, through the generation of androgenic steroids fuelling oncogenic signalling via the androgen receptor. These studies present mechanistic evidence of how the host microbiota might be implicated in prostate carcinogenesis and tumour progression. Importantly, these findings also reveal potential avenues for the detection and treatment of prostate cancer through the profiling and modulation of the host microbiota. The latter could involve approaches such as the use of faecal microbiota transplantation,prebiotics, probiotics, postbiotics or antibiotics, which can be used independently or combined with existing treatments to reverse therapeutic resistance and improve clinical outcomes in patients with prostate cancer.

Immunogenomic profiles associated with response to life-prolonging agents in prostate cancer.

Prostate cancer is the most commonly diagnosed cancer but the management of advanced prostate cancer remains a therapeutic challenge, despite the survival benefits imparted by several therapeutic discoveries targeting different molecular pathways. The mechanisms of resistance to androgen deprivation and tumour progression to lethal metastatic variants are often regulated by androgen receptor (AR) bypass mechanisms and/or neuroendocrine differentiation. Moreover, recent data also suggested the involvement of adaptive and innate infiltrated immune cells in prostate tumour progression. Improvements in cancer genome analyses contributed to a better understanding of antitumour immunity and provided solutions for targeting highly cancer-specific neoantigens generated from somatic mutations in individual patients. In this review, we investigated the current knowledge on the interplay between cancer development and the complex mechanisms of immune regulation. Particularly, we focused on the role of tumour immune microenvironment, generally characterised by strong barriers for immunotherapy, and we discuss the rationale for the potential application of single agent and combination immune-targeting strategies that could lead to improved outcomes. Careful selection based on clinical and genomic factors may allow identification of patients who could benefit from this treatment approach in multiple settings (from localised to advanced prostate tumour) and in different histological subtypes (from adenocarcinoma to neuroendocrine prostate cancer).

Retracted] TRIM16 suppresses the progression of prostate tumors by inhibiting the Snail signaling pathway.

Following the publication of this paper, it was drawn to the Editor's attention by concerned readers that the western blotting data shown in Figs.4C and7B and D, the scratch‑wound assay images shown in Figs.5A and 6A, and certain of the cell migration and invasion assay data shown in Figs.5B and 6B were strikingly similar to data that had previously appeared in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 38: 1734‑1742, 2016; DOI: 10.3892/ijmm.2016.2774].

Abstract A062: Alternative promoter usage is linked to transcriptional and epigenetic alterations during prostate cancer progression

Abstract Background: Prostate tumor progression is driven by transcription factors (TFs), most prominently the Androgen Receptor (AR), that drive proliferation and therapy resistance. Many genes have several promoters that can be bound by distinct TFs. It is unclear what role alternative promoter selection plays in tumor progression. We hypothesized that driver TFs target novel gene promoters during prostate tumor progression, and that understanding how this targeting occurs would reveal novel aspects of prostate tumor biology. Methods: We performed ultra-deep RNA sequencing on 104 metastatic Castration Resistant Prostate Cancer (mCRPC) biopsies, generating > 450M reads/sample (10X the typical depth), in samples with matched whole genome DNA and methylation sequencing. We combined these data with published deep transcriptomes in normal prostate and localized prostate cancer for a total of 274 samples. Promoter activity was evaluated in all 274 biopsies using the proActiv tool. Differential promoter activity levels were integrated with transcription factor motif enrichment, chromatin immunoprecipitation sequencing, and previously published somatic and methylation sequencing data in the mCRPC samples. Results: Using normal prostate tissue as a baseline, we identified 463 and 3,237 APs with differential activity in localized prostate cancer and mCRPC, respectively. Increased alternative promoter (AP) usage was associated with upregulation of prostate tumor driver genes. Elevated androgen signaling in both localized and mCRPC was correlated with increased AP use. In localized prostate tumors, APs preferentially switch to promoters harboring binding sites for the AR pioneer factor FOXA1. In mCPRC, APs were further enriched for binding of MYC, E2F1, and HIF1A. Furthermore, AP usage reflects transcriptional dysregulation related to lineage plasticity in response to therapy. APs in neuroendocrine prostate cancer (NEPC) were bound by neuroendocrine TFs such as ASCL1 and HAND2. While canonical promoters are usually unmethylated, methylation levels at APs were strongly linked to AP activity. Conclusions: Our data show that transcription initiated at APs is a key contributor to increased gene activity in prostate tumors. APs that are upregulated in prostate tumors are linked to transcription factors activated by recurrent somatic alterations and lineage plasticity. Methylation at APs is an important and underappreciated driver of promoter choice in mCRPC. Understanding how somatic alterations and epigenetic reprogramming of TFs affect APs is essential to understanding how these processes impact therapy resistance. Citation Format: Meng Zhang, Martin Sjöström, Raunak Shrestha, Arian Lundberg, Thaidy Moreno-Rodriguez, Adam Foye, Ha X. Dang, Joshi J. Alumkal, Rahul Aggarwal, Eric J. Small, Christopher A. Maher, Felix Y. Feng, David Quigley. Alternative promoter usage is linked to transcriptional and epigenetic alterations during prostate cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A062.

Antiproliferative activity of marine-derived oligopeptides combined with androgen receptor inhibition in preclinical prostate cancer models.

e15186 Background: Recent cancer statistics reveal a sustained increase in the incidence of prostate cancer (PC) of 3% per year. More than half of this increase is attributable to advanced disease. Advanced PC remains largely incurable, owing to inevitable progression. Escalation of therapy can restore tumor control, but significant sequelae may result. Anticancer peptides of marine origin appear intrinsically target specific and may constitute a novel approach to improve the therapeutic sensitivity of resistant cancers. Recently published in vitro work showed that a marine soluble protein hydrolysate (SPH) potentiated the anticancer effect of androgen-receptor inhibitors (ARis) in PC cells. SPH also induced transcriptional upregulation of ferritin heavy chain 1 (FTH1) in LNCaP and PC3 cell lines. Given the growing recognition that iron dysmetabolism plays a key role in PC, we applied the findings to this current study. Methods: Eight candidate FTH1-modulatory peptides (FT-001 to -008, all 7- or 8-mer peptides) were identified in the SPH peptide mix and subsequently sequenced and synthesized. Antiproliferative effects of individual FT peptides were assessed in combination with ARis (bicalutamide/BIC or enzalutamide/ENZ) in phenotypically distinct PC cell lines (LNCaP, PC3, VCaP, ENZR-VCaP) and compared to the inhibitory effect of SPH-ARi combination or ARi monotherapy. Results: FT-002 or -005 (10 μM concentration), showed significantly greater inhibition of LNCaP and PC3 cell viability when co-administered with BIC IC50 (0.4 μM & 10 μM respectively), than SPH (160 μM) with BIC or BIC monotherapy (p < 0.001). Similarly, either peptide combined with ENZ IC50 (1.4 μM) exhibited significant antiproliferative effects on androgen-sensitive VCaP cells when compared to SPH (160 μM) & ENZ co-treatment (p < 0.01) and ENZ monotreatment (p < 0.001). Both peptides (10 μM) produced a similar pattern of results in ENZ-resistant VCaP cells when treated with ENZ at its corresponding IC50 (47 μM) (p < 0.001). Differential gene expression profiling of all tested cells showed a consistent and significant upregulation of FTH1 and concomitant downregulation of transferrin receptor (TFRC) gene expression of greater than 2-fold for FT/ARi therapy. Conclusions: FT-002 and -005 synergistically combine with ARis to significantly attenuate PC tumor growth in vitro. Gene expression profiling implicates peptide-mediated FTH1 and TFRC modulation in the mode of action to interfere with tumor cell iron metabolism. Novel research perspectives implicate ferritin and FTH1 expression levels in prostate carcinogenesis and tumor progression. Further research in xenograft models is warranted, in order to validate the current findings and further investigate the cellular pathways responsible for the observed anticancer activity seen with FT-002 and FT-005.

Abstract 4246: Synergistic inhibition of prostate tumor growth and progression by the combination of curcumin and ursolic acid in HiMyc mice

Abstract Prostate cancer (PCa) is the second leading cause of cancer death among men in the United States. According to the World Health Organization, approximately one-third of all cancer deaths could be prevented through an increased consumption of natural compounds. Through the use of a two-tiered screening method in PCa cells (depletion of cellular ATP level followed by glutamine uptake) of a phytochemical library, curcumin and ursolic acid were selected for further investigation. Twenty-four hour treatment of LNCaP, 22Rv1 and HMVP2 cells with the combination resulted in significant decreases in expression of members of the miR-17-92 and miR-106b-25 clusters, which are upregulated in PCa and have been shown to be involved in tumorigenesis, cell survival, and metastasis. In the HiMyc mouse model, where mice spontaneously develop primary PCa, supplementing diets with the combination of curcumin (1%) and ursolic acid (0.2%) resulted in significant inhibition of tumor growth and progression compared to diets containing either compound alone. There were no differences in body weight or food consumption in any of the diet groups during the tumor experiment. The current data suggests that the combination of curcumin and ursolic acid synergistically inhibits PCa growth and progression in HiMyc mice, which may be in part due to their effects on microRNA expression. Ongoing studies are further examining the role of specific miRNAs as well as oncogenic signaling pathways potentially involved in the mechanism of synergistic chemopreventive action of this combination. The current data suggest that this novel combination could be a valuable therapeutic option for prevention and/or treatment of PCa. Funding: This work was supported by NIH Grant CA228404. Citation Format: Chelsea A. Friedman, Achinto Saha, John DiGiovanni. Synergistic inhibition of prostate tumor growth and progression by the combination of curcumin and ursolic acid in HiMyc mice. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4246.

Abstract 1603: The effect of dickkopf-1 (DKK-1) on prostate cancer growth and bone metastasis using the canine osteoblastic Probasco cell line

Abstract Osteoblastic bone metastasis is the predominant phenotype observed in advanced prostate cancer and is associated with high patient mortality and morbidity. WNT signaling is necessary for both bone formation and tumor progression. Dickkopf-1 (DKK-1), a secretory antagonist of the canonical WNT/β-catenin signaling pathway, plays a complex role in bone tumors since it can either promote or decrease tumor occurrence and metastasis. The present study explored the molecular role of DKK-1 in prostate tumor progression, metastasis, and tumor-bone interactions using the osteoblastic canine prostate cancer cell line, Probasco. Previously, we found that DKK-1 can inhibit bone mineralization of mouse calvaria by Probasco conditioned medium (CM). Now we stably expressed DKK-1 in Probasco cells (Probasco-DKK-1), which were injected into the tibias or left ventricle of athymic mice. Bone metastases were monitored by bioluminesent imaging, microCT, and histopathology. Our results showed that Probasco-DKK-1 bone metastases had increased tumor growth, increased osteoclastic bone resorption, and decreased intramedullary woven bone formation in vivo. In vitro, DKK-1 had an autocrine effect on Probasco cells, which altered the cell morphology, increased cell proliferation, and induced EMT. Mechanistically, DKK-1 had little effect on the canonical WNT/β-catenin signaling while dramatically down-regulated the non-canonical WNT/JNK signaling, which inhibited caspase-dependent apoptosis in Probasco-DKK-1 cells. To investigate the effect of Probasco-DKK-1 on bone cells, primary osteoblasts and osteoclasts were treated by CM collected from cancer cells. We found that DKK-1 did not inhibit the mineralization of osteoblasts nor stimulate the activity of osteoclasts directly, but the expression of RNAKL was significantly higher in Probasco-DKK-1 CM-treated osteoblasts. Therefore, the Probasco-DKK-1 cells enhanced the activity of osteoclasts indirectly via the regulation of osteoblasts, which induced bone resorption. In conclusion, we showed that DKK-1 promoted prostate tumor growth by stimulating cell proliferation and inhibiting apoptosis in a canonical WNT-independent manner and attenuated the osteoblastic activity of prostate cancer. These findings provide new insights into the molecular mechanisms of DKK-1 in tumor progression. Citation Format: Shiyu Yuan, Nathan K. Hoggard, Noriko Kantake, Blake E. Hildreth, Thomas J. Rosol. The effect of dickkopf-1 (DKK-1) on prostate cancer growth and bone metastasis using the canine osteoblastic Probasco cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1603.

Prostate cancer cell‑derived spondin 2 boosts osteogenic factor levels in osteoblasts via the PI3K/AKT/mTOR pathway.

Prostate cancer is the leading cause of cancer death among men worldwide. Bone metastasis is one of the main problems arising from prostate cancer. Spondin 2 is a diagnostic marker specific for prostate cancer; however, the role of spondin 2 in prostate cancer‑driven osteogenesis remains unclear. The present study was carried out to explore the role of spondin 2 on prostate cancer cell‑induced osteogenesis. In the present study, the expression of spondin 2 was analyzed in prostate cancer samples obtained from Gene Expression Omnibus. The supernatant of prostate cancer cells was used to treat the osteoblast precursor MC3T3‑E1 cell line to determine the effect of spondin 2 on osteoblasts. The effect of spondin 2 on osteogenic factor production was also examined after neutralization with a spondin 2 antibody invitro via reverse transcription‑quantitative PCR. Furthermore, the effect of spondin 2 on the PI3K/AKT/mTOR pathway was assessed using a patient dataset from The Cancer Genome Atlas and invitro via western blot analysis. In addition, an inhibitor of spondin 2 receptor (ATN‑161) was used to explore the inhibition effect of spondin 2 receptor in MC3T3‑E1 cells. The results showed that spondin 2 promoted Osterix and Runx2 expression in osteoblasts, and this process was tightly associated with the activation of the PI3K/AKT/mTOR pathway. Moreover, it was demonstrated that the function of spondin 2 on prostate cancer‑driven osteogenesis at least partly relied on the integrin receptor α5β1. These results demonstrated that spondin 2 boosts osteogenesis via the PI3K/AKT/mTOR pathway under conditions of prostate tumor progression.

Ciliary Neurotrophic Factor Modulates Multiple Downstream Signaling Pathways in Prostate Cancer Inhibiting Cell Invasiveness.

Prostate cancer (PCa) remains the most common diagnosed tumor and is the second-leading cause of cancer-related death in men. If the cancer is organ-confined it can be treated by various ablative therapies such as RP (radical prostatectomy), RT (radiation therapy), brachytherapy, cryosurgery or HIFU (High-Intensity Focused Ultrasound). However, advanced or metastatic PCa treatment requires systemic therapy involving androgen deprivation, but such patients typically progress to refractory disease designated as castration-resistant prostate cancer (CRPC). Interleukin-6 (IL-6) has been established as a driver of prostate carcinogenesis and tumor progression while less is known about the role of ciliary neurotrophic factor (CNTF), a member of the IL-6 cytokine family in prostate cancer. Moreover, MAPK/ERK, AKT/PI3K and Jak/STAT pathways that regulate proliferative, invasive and glucose-uptake processes in cancer progression are triggered by CNTF. We investigate CNTF and its receptor CNTFRα expressions in human androgen-responsive and castration-resistant prostate cancer (CRPC) by immunohistochemistry. Moreover, we investigated the role of CNTF in proliferative, invasive processes as well as glucose uptake using two cell models mimicking the PCa (LNCaP cell line) and CRPC (22Rv1 cell line). Our results showed that CNTF and CNTFRa were expressed in PCa and CRPC tissues and that CNTF has a pivotal role in prostate cancer environment remodeling and as a negative modulator of invasion processes of CRPC cell models.

Targeting PI3K/Akt signaling in prostate cancer therapy.

Urological cancers have obtained much attention in recent years due to their mortality and morbidity. The most common and malignant tumor of urological cancers is prostate cancer that imposes high socioeconomic costs on public life and androgen-deprivation therapy, surgery, and combination of chemotherapy and radiotherapy are employed in its treatment. PI3K/Akt signaling is an oncogenic pathway responsible for migration, proliferation and drug resistance in various cancers. In the present review, the role of PI3K/Akt signaling in prostate cancer progression is highlighted. The activation of PI3K/Akt signaling occurs in prostate cancer, while PTEN as inhibitor of PI3K/Akt shows down-regulation. Stimulation of PI3K/Akt signaling promotes survival of prostate tumor cells and prevents apoptosis. The cell cycle progression and proliferation rate of prostate tumor cells increase by PI3K/Akt signaling induction. PI3K/Akt signaling stimulates EMT and enhances metastasis of prostate tumor cells. Silencing PI3K/Akt signaling impairs growth and metastasis of prostate tumor cells. Activation of PI3K/Akt signaling mediates drug resistance and reduces radio-sensitivity of prostate tumor cells. Anti-tumor compounds suppress PI3K/Akt signaling in impairing prostate tumor progression. Furthermore, upstream regulators such as miRNAs, lncRNAs and circRNAs regulate PI3K/Akt signaling and it has clinical implications for prostate cancer patients.

The Emergence of Cancer Stem Cells in Early Diagnosed Prostate Cancer

The Emergence of Cancer Stem Cells in Early Diagnosed Prostate Cancer

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer.

There is an urgent need for exploring new actionable targets other than androgen receptor to improve outcome from lethal castration-resistant prostate cancer. Tumor metabolism has reemerged as a hallmark of cancer that drives and supports oncogenesis. In this regard, it is important to understand the relationship between distinctive metabolic features, androgen receptor signaling, genetic drivers in prostate cancer, and the tumor microenvironment (symbiotic and competitive metabolic interactions) to identify metabolic vulnerabilities. We explore the links between metabolism and gene regulation, and thus the unique metabolic signatures that define the malignant phenotypes at given stages of prostate tumor progression. We also provide an overview of current metabolism-based pharmacological strategies to be developed or repurposed for metabolism-based therapeutics for castration-resistant prostate cancer.

Differential impact of PI3K/AKT/mTOR signaling on tumor initiation and progression in animal models of prostate cancer.

The PI3K/AKT/mTOR signaling pathway is essential for initiation and progression of prostate cancer. However, there has been no a comprehensive comparison for the role of these signaling nodes in prostate tumor initiation and progression. With genetically engineered animal models, we compared the impact of prostate-specific deletions of Pten, Tsc1, and Tsc2 and activation of Akt1 on tumor initiation and progression. Also, we assessed the expression and genetic alterations of PTEN, AKT1, TSC1, and TSC2 in human primary prostate cancers. For the genetically engineered mice, prostate conditional knockout (cKO) of Pten, Tsc1, and Tsc2 led to initiation and progression of mouse prostatic neoplasia hyperplasia (mPIN). Akt1 transgenic mice developed more aggressive mPINs than mice with Tsc1 or Tsc2 single-cKO, but the effect was more moderate than that for Pten single-cKO or Tsc1/Tsc2 double-cKO mice. Functional analyses showed that Pten single-cKO, AKT1 activation, and Tsc1/Tsc2 double-cKO induced cell proliferation more than Tsc1 or Tsc2 single-cKO, but only Pten single-cKO and AKT1 activation reduced epithelial adhesion. All cKO or AKT1 activation enhanced the phosphorylation of p-S6 (S235/236) but only Pten single-cKO and Tsc1/Tsc2 double-cKO enhanced the phosphorylation of p-AKT (S473) and p-4EBP1 (T37/46/70). In human prostate cancers, PTEN, but not AKT1, TSC1, or TSC2 had frequent genetic alterations. However, as key signaling nodes, AKT1, TSC1, and TSC2 may be responsible for PTEN loss-mediated tumor initiation and progression. Our results for genetically engineered mouse models suggest a differential role of the PI3K/AKT/mTOR signaling nodes in prostate cancer initiation and progression, but the underlying molecular mechanisms remain unaddressed.

The Androgen Receptor and Its Crosstalk With the Src Kinase During Castrate-Resistant Prostate Cancer Progression.

While the androgen receptor (AR) signalling is the mainstay therapeutic target for metastatic prostate cancers, these tumours will inevitably develop therapy resistance to AR pathway inhibitors suggesting that prostate tumour cells possess the capability to develop mechanisms to bypass their dependency on androgens and/or AR to survive and progress. In many studies, protein kinases such as Src are reported to promote prostate tumour progression. Specifically, the pro-oncogene tyrosine Src kinase regulates prostate cancer cell proliferation, adhesion, invasion, and metastasis. Not only can Src be activated under androgen depletion, low androgen, and supraphysiological androgen conditions, but also through crosstalk with other oncogenic pathways. Reciprocal activations between Src and AR proteins had also been reported. These findings rationalize Src inhibitors to be used to treat castrate-resistant prostate tumours. Although several Src inhibitors had advanced to clinical trials, the failure to observe patient benefits from these studies suggests that further evaluation of the roles of Src in prostate tumours is required. Here, we summarize the interplay between Src and AR signalling during castrate-resistant prostate cancer progression to provide insights on possible approaches to treat prostate cancer patients.

Abstract 5468: A pharmacological inhibition of sterol O-acyltransferase 1improves response to enzalutamide in prostate cancer

Abstract Prostate cancer (PCa) growth is mediated by androgens via activation of androgen receptor (AR). Accordingly, androgen deprivation therapy (ADT) is the gold standard for the treatment of advanced PCa, but progression to castration-resistant PCa (CRPC) follows. Enzalutamide (ENZ) is an AR antagonist used for the management of CRPC. However, patients acquire resistance to the drug in a short period. Meanwhile, cholesterol is a precursor to androgen and its metabolism is dysregulated in PCa. In addition, cholesteryl ester (CE) accumulation aggravates tumor growth but its association with ENZ treatment has not been studied. Thus, we hypothesized that inhibition of CE formation by blockage of sterol-O-acyltransferase 1 (SOAT1) could enhance the response to ENZ. We found that SOAT1 mRNA is upregulated in clinical prostate tumors compared to normal/benign tissues in TCGA dataset. SOAT1 mRNA level was also highly correlated with AR expression in SU2CF/PCF cohorts and TCGA dataset, suggesting critical role of the cholesterol metabolism in prostate tumor progression and potential association to AR signaling pathway. We treated 22RV1 prostate cancer cells with ENZ in the presence or absence of SOAT1 inhibitor, avasimibe, and found the combination treatment effectively reduced the level of CEs compared to control, which accompanied inhibition of colony formation and cell proliferation. Combination index value was calculated and the relationship between the two drugs showed synergism. Furthermore, genetic knockdown of SOAT1 sensitized cells to ENZ treatment and also reduced the number of colonies formed. In TCGA dataset, patients who had previously undergone ADT were analyzed, and their Kaplan-Meier survival curve showed low SOAT1 expressing patients had a significantly longer progression-free survival rate than their counterpart, indicating that SOAT1 could act as a prognostic biomarker predicting PCa treatment outcome. Gene set enrichment analysis of patients with ADT history showed androgen response gen sets were enriched in high SOAT1 expressing PCa patient group. Inhibition of SOAT1 and the combination treatment did not change AR and ARV7 protein level, but downstream genes such as PSA were down regulated upon the combination treatment. In summary, our in vitro results showed blockage of SOAT1 enzyme sensitized PCa cells to ENZ treatment and analysis of PCa patient data suggested that SOAT1 gene expression has potential as a prognostic marker. Citation Format: Sora Q. Kim, Sagar Utturkar, Nadia M. Atallah, Kee-Hong Kim. A pharmacological inhibition of sterol O-acyltransferase 1improves response to enzalutamide in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5468.

Abstract 2510: An atlas of single-cell and spatial transcriptomics reveals alterations that correlate with human prostate cancer progression

Abstract Most systemic therapies for prostate cancer target androgen receptor signaling. Given the ongoing disease burden and mortality from advanced prostate cancer that persist despite available therapies, novel therapeutic targets are clearly needed. To this end, we conducted a high-resolution analysis of primary prostate cancer samples across a spectrum of tumor stage using 10x Chromium scRNAseq. Within each patient, we compared the prostate tumor to its adjacent normal tissue. These samples were also compared to healthy prostate samples collected from patients whose prostates were removed in the setting of bladder cancer surgery. Joint analysis revealed a rich repertoire of immune and non-immune stroma cells. Significant alterations were apparent in the prostate tumor microenvironment compared to adjacent normal and healthy samples. One striking difference was an expansion of T-cell cluster characterized by decreased cytotoxic and an increased exhaustion gene signatures. Another difference was the significantly higher regulatory T cell (Treg) activity. There was a substantial population shift within the myeloid compartment. Specifically, tumor tissue showed a selective enrichment in M2-like macrophages which was validated by multiplex immunohistochemistry. In addition, tumor tissue showed a significant increase in the myeloid-derived suppressor cell scoring in tumor inflammatory monocytes that strongly correlated with Treg activity. The changes in both myeloid and T cell gene expression suggest an immune suppressive environment within the tumor. In addition, we performed Slide-seqV2 to generate high spatial resolution maps of cellular organization of prostate tissues. The highly detailed spatial configuration of the healthy prostate tissue showed well-organized prostate epithelial glands surrounded by immune and non-immune stromal cells. This tissue architecture was severely disrupted within the cancerous prostate. Endothelial and fibroblast populations were disorganized and dispersed throughout the invading tumor. Context-dependent differential expression gene analysis on endothelial cells showed significant upregulation of sprouting angiogenesis and vascular endothelial growth factor pathways in the tumor context. In addition, we developed an approach to characterize the coordination between tumor cells and stromal compartment via spatial ligand-receptor (L/R) interaction. Data revealed 405 significant potential communication channels with many of these interactions known to have a role in prostate tumor angiogenesis and progression. These data provide a high resolution landscape of localized prostate cancer via 10x and Slide-seq. Data showed an immunosuppressive milieu in addition to highly active endothelial angiogenic program. L/R interaction analysis revealed interactions that may serve as potential therapeutic targets. Citation Format: Taghreed Hirz, Shenglin Mei, Hirak Sarkar, Youmna Kfoury, Shulin Wu, Chin-Lee Wu, Fei Chen, Evan Z. Macosko, Douglas M. Dahl, Ninib Baryawno, David T. Scadden, Philip J. Saylor, Peter V. Kharchenko, David B. Sykes. An atlas of single-cell and spatial transcriptomics reveals alterations that correlate with human prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2510.