Impact of Metastatic Microenvironment on Physiology and Metabolism of Small Cell Neuroendocrine Prostate Cancer Patient-Derived Xenografts

TL;DR

This study explores how the liver and bone environments affect the behavior of aggressive prostate cancer in mice, aiming to improve diagnosis and treatment.

Contribution

The study reveals how tumor microenvironments in the liver and bone influence cancer metabolism and physiology using advanced imaging techniques.

Findings

Liver tumors showed consistent metabolic markers, while bone tumors were influenced by interactions with bone cells.

Combined MRI techniques are needed to accurately assess tumor characteristics before treatment.

Understanding microenvironment effects could lead to better treatment strategies for metastatic prostate cancer.

Abstract

Powerful drugs targeting androgen receptors can trigger a very aggressive form of metastatic prostate cancer known as small cell neuroendocrine prostate cancer (SCNC). This type of cancer is tough to treat and has a poor survival rate, especially when it spreads to the liver, compared to when it spreads only to the bones. The objective was to understand why SCNC tumors behave differently in the liver versus the bones, which is critical for improving how we diagnose and treat this severe cancer using imaging. To this end, the same SCNC cells derived from patients were implanted in mouse bone and liver, and many different parameters were investigated using magnetic resonance technology. The results showed that the metabolic activity of cancer cells in the liver matched certain biochemical markers, whereas in the bones, these markers were influenced by interactions with bone cells. These findings suggest that the tumor’s environment significantly affects its characteristics, and hence, it is essential to use a combination of imaging methods to accurately assess the tumor before treatment. This approach could lead to better treatment strategies and improve the evaluation of how well treatments are working. By understanding these mechanisms, researchers can develop new ways to image and treat cancer, potentially leading to more effective therapies for patients with metastatic prostate cancer. This research is crucial for advancing cancer treatment and could have a significant impact on the medical community’s approach to managing aggressive cancer types.

Background: Potent androgen receptor pathway inhibitors induce small cell neuroendocrine prostate cancer (SCNC), a highly aggressive subtype of metastatic androgen deprivation-resistant prostate cancer (ARPC) with limited treatment options and poor survival rates. Patients with metastases in the liver have a poor prognosis relative to those with bone metastases alone. The mechanisms that underlie the different behavior of ARPC in bone vs. liver may involve factors intrinsic to the tumor cell, tumor microenvironment, and/or systemic factors, and identifying these factors is critical to improved diagnosis and treatment of SCNC. Metabolic reprogramming is a fundamental strategy of tumor cells to colonize and proliferate in microenvironments distinct from the primary site. Understanding the metabolic plasticity of cancer cells may reveal novel approaches to imaging and treating metastases more effectively. Methods: Using magnetic resonance (MR) imaging and spectroscopy, we interrogated the physiological and metabolic characteristics of SCNC patient-derived xenografts (PDXs) propagated in the bone and liver, and used correlative biochemical, immunohistochemical, and transcriptomic measures to understand the biological underpinnings of the observed imaging metrics. Results: We found that the influence of the microenvironment on physiologic measures using MRI was variable among PDXs. However, the MR measure of glycolytic capacity in the liver using hyperpolarized 13C pyruvic acid recapitulated the enzyme activity (lactate dehydrogenase), cofactor (nicotinamide adenine dinucleotide), and stable isotope measures of fractional enrichment of lactate. While in the bone, the congruence of the glycolytic components was lost and potentially weighted by the interaction of cancer cells with osteoclasts/osteoblasts. Conclusion: While there was little impact of microenvironmental factors on metabolism, the physiological measures (cellularity and perfusion) are highly variable and necessitate the use of combined hyperpolarized 13C MRI and multiparametric (anatomic, diffusion-, and perfusion- weighted) 1H MRI to better characterize pre-treatment tumor characteristics, which will be crucial to evaluate treatment response.

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