Pan-Cancer Survey of Tumor Mass Dormancy and Underlying Mutational Processes.

Anna Julia Wiecek,Maria Secrier,Daniel Hadar Jacobson,Wojciech Lason

doi:10.3389/fcell.2021.698659

Abstract

Tumor mass dormancy is the key intermediate step between immune surveillance and cancer progression, yet due to its transitory nature it has been difficult to capture and characterize. Little is understood of its prevalence across cancer types and of the mutational background that may favor such a state. While this balance is finely tuned internally by the equilibrium between cell proliferation and cell death, the main external factors contributing to tumor mass dormancy are immunological and angiogenic. To understand the genomic and cellular context in which tumor mass dormancy may develop, we comprehensively profiled signals of immune and angiogenic dormancy in 9,631 cancers from the Cancer Genome Atlas and linked them to tumor mutagenesis. We find evidence for immunological and angiogenic dormancy-like signals in 16.5% of bulk sequenced tumors, with a frequency of up to 33% in certain tissues. Mutations in the CASP8 and HRAS oncogenes were positively selected in dormant tumors, suggesting an evolutionary pressure for controlling cell growth/apoptosis signals. By surveying the mutational damage patterns left in the genome by known cancer risk factors, we found that aging-induced mutations were relatively depleted in these tumors, while patterns of smoking and defective base excision repair were linked with increased tumor mass dormancy. Furthermore, we identified a link between APOBEC mutagenesis and dormancy, which comes in conjunction with immune exhaustion and may partly depend on the expression of the angiogenesis regulator PLG as well as interferon and chemokine signals. Tumor mass dormancy also appeared to be impaired in hypoxic conditions in the majority of cancers. The microenvironment of dormant cancers was enriched in cytotoxic and regulatory T cells, as expected, but also in macrophages and showed a reduction in inflammatory Th17 signals. Finally, tumor mass dormancy was linked with improved patient survival outcomes. Our analysis sheds light onto the complex interplay between dormancy, exhaustion, APOBEC activity and hypoxia, and sets directions for future mechanistic explorations.

Highlights

Tumor evolution is shaped by a variety of internal and external forces that act at different stages during cancer development, sometimes in an antagonistic manner, and drive distinct trajectories to advanced disease (Gerlinger et al, 2014; McGranahan and Swanton, 2017; Temko et al, 2018)
Cellular dormancy driven by arrest in the G0 state of the cell cycle (Phan and Croucher, 2020), and tumor mass dormancy (TMD), described as an equilibrium between cell proliferation and cell death shaped by the microenvironment that constrains tumor growth (Holmgren et al, 1995; Aguirre-Ghiso, 2007; Wang et al, 2019), are complementary but distinct mechanisms that contribute to the plasticity of cancer expansion (Shen and Clairambault, 2020; Huang, 2021)
Immunological and angiogenic dormancy program scores were assigned on a per-sample basis using two distinct methodologies that exploited the expression of genes associated with either process, focusing either on differences between up/downregulated gene activity (‘scaled difference of means’) or on the largest variation explained by principal component analysis (‘PCA’)

Summary

Introduction

Tumor evolution is shaped by a variety of internal and external forces that act at different stages during cancer development, sometimes in an antagonistic manner, and drive distinct trajectories to advanced disease (Gerlinger et al, 2014; McGranahan and Swanton, 2017; Temko et al, 2018). Cellular dormancy driven by arrest in the G0 state of the cell cycle (Phan and Croucher, 2020), and tumor mass dormancy (TMD), described as an equilibrium between cell proliferation and cell death shaped by the microenvironment that constrains tumor growth (Holmgren et al, 1995; Aguirre-Ghiso, 2007; Wang et al, 2019), are complementary but distinct mechanisms that contribute to the plasticity of cancer expansion (Shen and Clairambault, 2020; Huang, 2021) The former concept had already been coined by Hadfield (1954) and has since led to the generation of more detailed mechanistic insights explaining its regulation by the DREAM complex (Sadasivam and DeCaprio, 2013; MacDonald et al, 2017; Kim et al, 2021), with key dependencies on the p53/p21 activation axis (Itahana et al, 2002; Barr et al, 2017; Heldt et al, 2018). The latter, initially termed “population dormancy” by Gimbrone et al (1972) and renamed to tumor mass dormancy, remains poorly understood due to the lack of suitable data and models (Boire et al, 2019)

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