A developmental constraint model of cancer cell states and tumor heterogeneity

Abstract

Cancer is a disease that stems from a fundamental liability inherent to multicellular life forms in which an individual cell is capable of reneging on the interests of the collective organism. Although cancer is commonly described as an evolutionary process, a less appreciated aspect of tumorigenesis may be the constraints imposed by the organism's developmental programs. Recent work from single-cell transcriptomic analyses across a range of cancer types has revealed the recurrence, plasticity, and co-option of distinct cellular states among cancer cell populations. Here, we note that across diverse cancer types, the observed cell states are proximate within the developmental hierarchy of the cell of origin. We thus posit a model by which cancer cell states are directly constrained by the organism's "developmental map." According to this model, a population of cancer cells traverses the developmental map, thereby generating a heterogeneous set of states whose interactions underpin emergent tumor behavior.

Keywords: cancer cell states; cellular plasticity; developmental constraints; tumor heterogeneity; tumorigenesis.

Figure 1.. Correspondence between lung cell types in development and cancer cell states in lung adenocarcinoma.

a, An illustration of dimensionality reduction projections of single-cell transcriptomic data from normal lung and mouse embryonic developmental atlases, which were used to generate the developmental hierarchy of cell types shown in c. b, Same as a, for cell identity-related cancer cell states in lung adenocarcinoma, as curated from single-cell transcriptomic studies^,,. c, (Top) A simplified developmental hierarchy of cell types identified using the approach diagrammed in a, within the foregut branch. Marker genes are indicated for relevant developmental cell types. (Bottom) Lung adenocarcinoma cancer cell states identified using the approach diagrammed in b, are arranged according to the developmental hierarchy, matched by corresponding gene expression programs.

Figure 2.. The developmental map constrains the occurrence of cancer cell states in seven cancer types.

(Top) A simplified developmental lineage of cell types based on a singlecell transcriptomic atlas of mouse embryonic development and tissue-specific reviews for pancreas, lung,^, skin,^, brain, muscles, and blood lineages. (Bottom) A synthesis of cancer cell states as detected in 7 cancer types. To generate this map, we first curated a list of single-cell transcriptomic atlases for each cancer type: pancreatic ductal adenocarcinoma,^, lung adenocarcinoma,^,, lung squamous cell carcinoma, melanoma,^,,, glioblastoma, acute myeloid leukemia,,, and rhabdomyosarcomas. Second, we curated lists of the identified cancer cell states that are related to cell identity and excluded those related to biological processes (such as cycling and stress). Finally, we arranged the cancer cell states in accordance with the developmental map. Arrows indicate evidenced cell state transitions. Stars indicate the purported cell of origin. Developmental cell type and cancer cell states are colored by cancer type.