Form Follows Function: A New Paradigm of Pancreatic Cancer Progression

Authors:
  • WGWilliam Gasper
    William Gasper
  • GPGiada Pontecorvi
    Giada Pontecorvi
  • ZCZhikai Chi
    Zhikai Chi
  • SESebastian Enrico
    Sebastian Enrico
  • LGLily Goodman
    Lily Goodman
  • HAHaneen Amarneh
    Haneen Amarneh
  • EMEvelyn Mazzarelli
    Evelyn Mazzarelli
  • JTJoshua Thomas
    Joshua Thomas
  • LZLucia Zhang
    Lucia Zhang
  • RHRachel Handloser
    Rachel Handloser
  • SLSeth LeCates
    Seth LeCates
  • ATAna Lucia Tomescu
    Ana Lucia Tomescu
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) exhibits a distinctive propensity to invade nearby organs and infiltrate large blood vessels, even in the absence of distant metastasis. While the genetic and transcriptomic drivers of PDAC progression have been well studied, the mechanisms by which these molecular changes translate into functional, invasive behavior remain largely unknown. Here, we uncover a striking level of tissue organization, characterized by previously unrecognized spatial and geometric properties within and among tumor structures. Leveraging the first large-scale, AI-assisted, human-curated PDAC atlas from hematoxylin and eosin (H&E) images, we annotated, classified, and characterized 144,474 malignant and normal structures from treatment-naive (n=118) and neoadjuvant-treated PDAC patients (n=50). Additionally, we developed a new computational tool, SHAPE, to investigate PDAC aggressiveness through a comprehensive geometrization of cancer progression. Using traditional H&E-stained slides and three-dimensional (3D) tissue reconstruction experiments, we observed that invading tumor structures display an eccentric morphology with pronounced local angular coherence. These geometric and spatial properties revealed coherent architectural patterns, with invasive structures closely tracking vessels and nerves as they infiltrate surrounding tissue. Mechanistically, integration of morphological features from 39,045annotated tumor structures with whole-genome and RNA sequencing data revealed that PDACs with numerous eccentric structures exhibit increased copy number alterations (CNAs), loss of heterozygosity (LoH) on the p-arm of chromosome 17, and a quasi-mesenchymal/basal-like molecular subtype. Spatial transcriptomic analysis of 1,650 tumor structures from six additional PDAC patients further confirmed upregulation of invasive cellular programs within highly eccentric structures, such as epithelial-to-mesenchymal transition (EMT), angiogenesis, coagulation, and complement pathways, underscoring their infiltrative nature. Finally, cross-validation of our AI-based method enabled a fully automated, highly interpretable computational approach to assist pathologists and clinicians in evaluating neoadjuvant chemotherapy response, predicting patient survival, and guiding chemotherapy in adjuvant settings. Collectively, these findings deepen our understanding of PDAC progression, identify a new hallmark of tumor architecture, and pave the way for full integration of AI-driven morphology-based approaches into clinical workflows to improve the management of PDAC patients.
Funding Information
  • National Institutes of Health (5R37CA242070)
  • Cancer Prevention & Research of Texas (RR200023)