AAnet resolves a continuum of spatially-localized cell states to unveil intratumoral heterogeneity.

Identifying functionally important cell states and structure within heterogeneous tumors remains a significant biological and computational challenge. Current clustering or trajectory-based models are ill-equipped to address the notion that cancer cells reside along a phenotypic continuum. We present Archetypal Analysis network (AAnet), a neural network that learns archetypal states within a phenotypic continuum in single-cell data. Unlike traditional archetypal analysis, AAnet learns archetypes in simplex-shaped neural network latent space. Using pre-clinical models and clinical breast cancers, AAnet resolves distinct cell states and processes, including cell proliferation, hypoxia, metabolism and immune interactions. Primary tumor archetypes are recapitulated in matched liver, lung and lymph node metastases. Spatial transcriptomics reveal archetypal organization within the tumor, and, intra-archetypal mirroring between cancer and adjacent stromal cells. AAnet identifies GLUT3 within the hypoxic archetype that proves critical for tumor growth and metastasis. AAnet is a powerful tool, capturing complex, functional cell states from multimodal data.