Archetype tasks link intratumoral heterogeneity to plasticity in recalcitrant small cell lung cancer [Human tumor]

Intratumoral heterogeneity underlies cancer treatment resistance, but approaches to neutralize it remain elusive. Here, we recast heterogeneity in a systems perspective that considers cancer cell functional tasks inherited from cells of origin. We apply Archetype Analysis to bulk transcriptomics data from small cell lung cancer (SCLC), which forms tumors composed of neuroendocrine (NE) and non-neuroendocrine (non-NE) transcriptional subtypes. SCLC subtypes fit well in a 5-dimensional polytope whose vertices optimize tasks reminiscent of pulmonary NE cells, the SCLC normal counterpart, and include injury repair, slithering, and chemosensation. SCLC cells near a vertex are specialists for a task, while more distant cells are generalists, bearing gene signatures of multiple archetypes. Evolutionary theory and dynamical systems modeling suggest a division of labor strategy for adaptation to treatment, based on task trade-offs amongst specialists and generalists. Cell Transport Potential, a metric derived from single-cell RNA velocity, uncovers plasticity trends from specialists to generalists, and NE to non-NE subtypes. Transcription factor network simulations indicate that MYC overexpression increases plasticity by de-stabilizing NE subtypes. Framing heterogeneity in archetype space provides insights into transformative cancer treatments aimed at tumor cell plasticity. scRNA-seq on two human tumors