Unified tumor growth mechanisms from multimodel inference and dataset integration
Fig 2
Conclusions and hypotheses from literature build mechanistic hypothesis exploration space for tumor growth and development.
(A) Synthesis of what is currently known about SCLC subtypes, which have been divided into two overall phenotypes, neuroendocrine (NE) and Non-NE, and then further classified into subtypes based on transcription factor expression. [1] NE SCLC cells, which do not express HES1, transition into Non-NE cells, which do. [2] HES1+ cells release unidentified factors (gray circle) that support viability and growth of HES1- cells, and the two HES1+ and HES1- populations grow better together rather than separately. [3] Consensus across the field led to labeling SCLC phenotypic subtypes by the dominant transcription factor expressed in that subtype. [4] Subtype with transcriptional signature intermediate between NE and Non-NE, named SCLC-A2. [5] Phenotypic transitions occur in a hierarchical manner from SCLC-A to SCLC-N to SCLC-Y cells. (B)-(E) Candidate model examples representing SCLC biological hypotheses (Table 1). Here we indicate schematically how a population dynamics model can represent each biological hypothesis, as well as denote how the set of candidate models is built combinatorially, in order of (B)-(E). (B) Model topologies constructed with 2+ subtypes, with number of combinations per number of subtypes. There are 11 options total, and each of these move forward to choose one effect option from (C [1], [2], or [3]. (C) Subtype effect schema, where there are different effectors between candidates and different affected cellular actions. If there are effects (C [2] or [3]), model behaviors affected are chosen (choose (C [4] & [6], [4] & [7], or [5] & [6]). Whether effects present (C [2], [3]) or not (C [1]), the candidate moves forward to choose initiating subtype(s): each subtype in the model must follow (D [1], [2], or [3]) and corresponding transition schemes (E [1], [2]). (D, E) Initiation schemes (D) and potential transition schemes (E), where all subtypes in topology must be accessible either as initiating subtypes or via transitions (D), unidirectional transitions are those that follow a hierarchy (E, top left), and bidirectional transitions must be symmetrical when present (E, top right and bottom). A: ASCL1, Achaete-scute homolog 1; N: NEUROD1, neurogenic differentiation factor 1; H: HES1, Hes Family BHLH Transcription Factor 1; P: POU2F3, POU class 2 homeobox 3; Y: YAP1, yes-associated protein.