Abstract A029: Integrated modeling of renal cancer bone metastasis to illuminate tumor progression and therapy response
Authors: Barrios Sergio , Marsilio Luca , Maksimovic Stefan , Campbell Matthew , Casarin Stefano , Dondossola Eleonora 
Published: November 2024

Bone metastatic clear cell renal cell carcinoma (BM ccRCC) is a persistent clinical challenge and a source of significant morbidity and lethality for up to 40% of metastatic patients. Despite the recent approval of life-prolonging agents (antiangiogenic agents, immunotherapy) patients with BM ccRCC will eventually progress, due to emerging resistance. Bidirectional communication between tumor cells and bone stroma has emerged as a key determinant of disease progression and recurrence. However, a major challenge in addressing the black box of therapy response in bone is the lack of efficient and informative systems that allow us to analyze the heterotypic stromal-epithelial interaction, further complicated by the anatomical inaccessibility of bone. For these reasons, the evolution of the metastatic niche and its implications in therapy response remain elusive. In order to improve clinical results, it is critical to establish biologically informed pre-clinical models to provide a mechanistic understanding of tumor progression in bone and treatment outcomes. To this purpose, we have established clinically relevant models of ccRCC bone metastasis that span in vivo and ex vivo multiphoton microscopy (iMPM and eMPM), tissue engineered bone window systems, and computational oncology. iMPM displays both sensitivity and time-resolution to identify dynamic interactions between ccRCC cells and bone 3D adaptive niches, which support therapy response and resistance. However, iMPM in bone is limited due to its cortical thickness, increased light scattering, and complex topology. As a novel alternative, we created a tissue-engineered bone construct (TEBC) that, after direct implantation of cancer cells, is combined with an adjacent skin window, allowing for non- destructive intravital examination of tumor growth. To flank these in vivo dynamic analyses, we established a pipeline for ex vivo extraction of topological information related to the molecular and cellular niches involved in tumor progression and response to treatment (eMPM). This method allows reconstruction of whole lesions, including zones more distant from the bone interface, paired with an extensive panel of molecular markers. To further investigate the effects of a broad multi-parameter space on tumor regression or persistence upon treatment, in silico, we developed an in vivo-inspired agent-based model (ABM) of ccRCC in bone. A computational approach combined to ad hoc biological experimentation can refine the experimental design, test clinically relevant hypotheses (including impact of treatments on disease progression) and predict scenarios that guide biological testing towards more successful outcomes. Consequently, by integrating these approaches, we are currently studying the progression of the bone metastatic niche and its response to therapy, with the ultimate goal of overcoming therapy failure.

Citation Format: Sergio Barrios, Luca Marsilio, Stefan Maksimovic, Matthew Campbell, Stefano Casarin, Eleonora Dondossola. Integrated modeling of renal cancer bone metastasis to illuminate tumor progression and therapy response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A029.