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CancerZigZag is a novel seed-initialized diffusion model that generates candidate single-cell tumor-associated state clouds from unpaired healthy-like cell populations by iteratively perturbing and reversing diffusion in the latent space. This approach addresses the scarcity of longitudinal data in cancer single-cell studies by enabling exploratory generation of potential tumor-associated cell distributions without requiring paired measurements or classifier guidance. The framework successfully generated candidate clouds that mapped to tumor-derived reference populations across multiple cancer types, revealing context-dependent relationships between tumor-associated displacement and residual seed organization.
Unpaired healthy cells can be iteratively transformed into plausible tumor-associated cell states using a seed-anchored diffusion process, revealing context-specific progression landscapes.
Single-cell cancer datasets are predominantly cross-sectional and rarely provide paired or longitudinal observations linking individual healthy-like cells to tumor-associated states. We introduce CancerZigZag, a seed-initialized diffusion-based framework for exploratory generation of tumor-associated single-cell candidate clouds from unpaired epithelial cell populations. For each cancer context, a diffusion model is trained exclusively on tumor-derived epithelial cells and applied through repeated partial latent-space perturbation and reverse diffusion to held-out healthy-like seeds, generating stochastic candidate clouds without paired measurements or classifier guidance. We applied CancerZigZag to colorectal, breast, lung, and renal cell carcinoma contexts and explored parameter landscapes defined by perturbation depth and the number of ZigZag cycles. Across the reported operating configurations, candidate clouds contained outputs classified toward held-out tumor-derived reference populations for each evaluated seed. Residual seed-dependent organization varied across contexts, with the clearest structure in colorectal cancer, more modest organization in lung cancer, and limited cloud-level structure in breast and renal cell carcinoma. Representative candidates also showed directional concordance with transcriptional shifts observed between held-out healthy-like and tumor-derived reference populations. CancerZigZag is not interpreted as a model of deterministic healthy-to-tumor transformation or cellular progression. Instead, it provides a reference-informed framework for exploring tumor-associated candidate distributions from unpaired healthy-like seeds and quantifying the context-dependent relationship between tumor-associated displacement and residual seed dependence.