Multiscale Cross-Modal Mapping of Molecular, Pathologic, and Radiologic Phenotypes in Lipid-Deficient Clear Cell Renal CellCarcinoma

📝 Abstract

Author Contributions: XGP and WM conceptualized and designed the study and conducted the investigation. YC, DZ, KY, XW, XL, YG, LF, and XC collected the data. YC and DZ analyzed the data. YC, DZ, and KY wrote the original draft. XGP and WM have accessed and verified the data. XGP and WM provided supervision. All authors reviewed and approved the final version of the manuscript. All authors have full access to all the data in the study and have final responsibility for the decision to submit for publication.

💡 Analysis

Author Contributions: XGP and WM conceptualized and designed the study and conducted the investigation. YC, DZ, KY, XW, XL, YG, LF, and XC collected the data. YC and DZ analyzed the data. YC, DZ, and KY wrote the original draft. XGP and WM have accessed and verified the data. XGP and WM provided supervision. All authors reviewed and approved the final version of the manuscript. All authors have full access to all the data in the study and have final responsibility for the decision to submit for publication.

📄 Content

Multiscale Cross-Modal Mapping of Molecular, Pathologic, and Radiologic Phenotypes in Lipid-Deficient Clear Cell Renal Cell Carcinoma Ying Cui∗1, Dongzhe Zheng∗2, Ke Yu∗3, Xiyin Zheng4, Xiaorui Wang5, Xinxiang Li6, Yan Gu7, Lin Fu1, Xinyi Chen1, Wenjie Mei†8, and Xin-Gui Peng†1 1Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China 2Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, NJ 08544, USA 3School of Automation, Southeast University, Nanjing, 210096, China 4Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA 5Automation and Electrical Engineering College, Lanzhou University of Technology, Lanzhou, 730050, China 6The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230031, China 7Lianyungang First People’s Hospital, 182 Tongguan North Road, Lianyungang, 222002, China 8School of Robotics and Automation, Suzhou Campus, Nanjing University, 1520 Taihu Road, Suzhou, 215163, China December 18, 2025 ∗Contributed equally as the joint first authors. †Contributed equally as the joint last authors. Corresponding Authors: Xin-Gui Peng, MD, PhD (Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China. Email: xinguipeng@seu.edu.cn). Wenjie Mei, PhD (School of Robotics and Automation, Suzhou Campus, Nanjing University, 1520 Taihu Road, Suzhou, 215163, China. Email: mei.wenjie@nju.edu.cn). Author Contributions: XGP and WM conceptualized and designed the study and conducted the investi- gation. YC, DZ, KY, XW, XL, YG, LF, and XC collected the data. YC and DZ analyzed the data. YC, DZ, and KY wrote the original draft. XGP and WM have accessed and verified the data. XGP and WM provided supervision. All authors reviewed and approved the final version of the manuscript. All authors have full access to all the data in the study and have final responsibility for the decision to submit for publication. Conflict of Interest Disclosures: The authors have no conflicts to report. Founding: This study has received funding from the National Natural Science Foundation of China (82272064, 62403125), the Natural Science Foundation of Jiangsu Province (BK20221461, BK20241283), Zhongda Hospital Affiliated to Southeast University, Jiangsu Province High-Level Hospital Pairing Assis- tance Construction (zdlyg08). 1 arXiv:2512.14750v1 [q-bio.QM] 13 Dec 2025 Abstract Clear cell renal cell carcinoma (ccRCC) exhibits extensive intratumoral heterogeneity on multiple biological scales, contributing to variable clinical outcomes and limiting the effectiveness of conventional TNM staging, which highlights the urgent need for multiscale integrative analytic frameworks. The lipid-deficient de-clear cell differentiated (DCCD) ccRCC subtype, defined by multi-omics analyses, is associated with adverse out- comes even in early-stage disease. Here, we establish a hierarchical cross-scale framework for the preoperative identification of DCCD-ccRCC. At the highest layer, cross-modal mapping transferred molecular signatures to histological and CT phenotypes, establishing a molecular-to-pathology-to-radiology supervisory bridge. Within this framework, each modality-specific model is designed to mirror the inherent hierarchical structure of tumor biology. PathoDCCD captured multi-scale microscopic features, from cellular morphology and tissue architecture to meso-regional organization. RadioDCCD integrated complementary macroscopic information by combining whole-tumor and its habitat-subregions radiomics with a 2D maximal-section heterogeneity metric. These nested models enabled integrated molecular subtype prediction and clinical risk stratification. Across five cohorts totaling 1,659 patients, PathoDCCD reliably recapitulated molecular subtypes, while RadioDCCD provided reliable preoperative prediction. The consistent predictions identified patients with the poorest clinical outcomes. This cross-scale paradigm unifies molecular biology, computational pathol- ogy, and quantitative radiology into a biologically grounded strategy for preoperative noninvasive molecular phenotyping of ccRCC. Introduction Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cancer, exhibits pronounced bio- logical and clinical heterogeneity that contributes to substantial variability in patient outcomes [1]. Although TNM staging and pathological features remain central to current clinical decision-making, these metrics in- completely reflect the metabolic and spatial complexity of ccRCC [1]. As a result, a subset of patients categorized as early or intermediate stage still experience disease recurrence or progress

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