Testing cellular provenance in the cancer extracellular matrix

Composition, architecture, and mechanics are central descriptors of the tumor extracellular matrix (ECM), but they do not identify the cells that synthesized and deposited it. Cellular provenance should therefore be distinguished from production context, deposition context, post-secretory history, and final matrix state. The central causal question is whether producer identity or state creates a persistent functional difference after abundance, proteoform, location, processing, assembly, and receptor environment are accounted for. Current evidence remains compatible with three explanations. The producer-mediated determinant model invokes source-linked proteoforms, co-secretomes, deposition patterns, or assembly routes. The provenance-associated model treats producer identity as a marker of abundance, timing, location, or cell state. The provenance-independent model predicts functional equivalence once molecular and matrix states are matched. Studies of collagen I, tenascin C, and fibronectin reveal three recurring patterns: producer-linked proteoform differences, stage-dependent source replacement, and source redundancy or assembly dependence. Protein-level source attribution and source-specific necessity are increasingly feasible, but abundance- and location-matched reciprocal source exchange remains uncommon. Cellular provenance should therefore be treated as a falsifiable variable whose functional significance is traced to a measurable molecular, spatial, mechanical, or assembly mediator.