Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity

Abstract

SUMMARYCancers arise through a process of somatic evolution that can result in substantial sub-clonal heterogeneity within tumors. The mechanisms responsible for the coexistence of distinct sub-clones and the biological consequences of this coexistence remain poorly understood. Here we used a mouse xenograft model to investigate the impact of sub-clonal heterogeneity on tumor phenotypes and the competitive expansion of individual clones. We found that tumor growth can be driven by a minor cell subpopulation, which enhances the proliferation of all cells within a tumor by overcoming environmental constraints and yet can be outcompeted by faster proliferating competitors, resulting in tumor collapse. We then developed a mathematical modeling framework to identify the rules underlying the generation of intratumor clonal heterogeneity. We found that non-cell autonomous driving, together with clonal interference, stabilizes sub-clonal heterogeneity, thereby enabling inter-clonal interactions that can lead to new phenotypic traits.

Carcinogenesis of renal cell carcinoma reflected in HLA ligands: A novel approach for synergistic peptide vaccination design

“…Additionally, personalized approaches should be given priority: these can lead to individualized vaccine cocktails that encompass small but distinct differences in the biological characteristics of carcinomas due to intra-and inter-tumoral heterogeneity of tumor sub-clones. 14,15 To achieve this, our primary aim was to develop a new approach using network analysis of source proteins that represent HLA-restricted peptides, thereby enabling the identification of biological processes and pathways enriched in and exclusively presented on ccRCC and their metastasis. Subsequently, these network analyses should provide the basis for defining new TAAs and peptide vaccines.…”

“…[11][12][13] However, peptide vaccine design still lacks a sustainable approach to generate individualized vaccination cocktails that consist of several immunogenic tumor-associated antigens (TAAs) which is essential for adequately addressing intra-and intertumoral heterogeneity. 14,15 The most elegant approach to target this goal is the identification of mutated, immunogenic HLA-presented peptides, which have been discovered in mice transgenic for human MHC 16 and are shown to induce tumor rejection in sarcoma-bearing mice 17 but have not yet been identified in any other species. Alternative strategies are therefore required.…”

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

“…Clonal heterogeneity drives cancer progression and metastasis, and can dynamically affect the biology of the tumor as a whole [6]. Furthermore, the genetic diversity in solid tumors often results in temporary, limited responses to chemotherapeutics, which allows for various mechanisms of resistance to form [7].…”

Cancer evolution and heterogeneity

“…A xenograft model of chemokine‐producing transgenic mouse‐derived clones and parental clones was applied in a study by Marusyk et al43 In terms of the variability between the groups in morphology, proliferation, and vascularization, only chemokine (C‐C motif) ligand 5 (CCL5)‐ and interleukin 11 (IL‐11)‐overexpressing subclones were able to enhance tumor growth. Tumor progression is frequently limited by microenvironmental constraints that cannot be overcome by the autonomous increase in cell proliferation rates.…”