Advances in Mapping Tumor Progression from Precancer Atlases

Abstract

Tissue profiling technologies present opportunities for understanding transition from precancerous lesions to malignancy, which may impact risk stratification, prevention, and even cancer treatment. A human precancer atlas building effort is ongoing to tackle the significant challenge of decoding the heterogeneity among cells, specimens, and patients. Here, we discuss the findings resulting from atlases built across precancer types, including those found in colon, breast, lung, stomach, cervix, and skin, using bulk, single-cell, and spatial profiling strategies. We highlight two main themes that emerge across precancer types: the ordering of molecular events that occur during tumor progression and the fluctuation of microenvironmental response during precancer progression. We further highlight the key challenges of data integration across large cohorts of patients, and the need for computational tools to reliably annotate and quality control high-volume, high-dimensional data.

Figure 1.. Bulk, single-cell and spatial profiling of precancers.

(A) Bulk, (B) single cell, and (C) spatial profiling technologies can interrogate different aspects of a sample. Bulk technologies have low resolution. They are more suited for deciphering inter-sample differences, but they can be applied in a high throughput manner and have the most mature operation pipelines. Single- cell technologies can evaluate individual cells, and thus, can characterize intra-sample heterogeneity, enabling differences between cell types or cell states to be investigated. Single-cell technologies are more susceptible to data quality issues. Spatial profiling technologies uncover an additional layer of information within a sample, that of spatial organization, enabling examination of spatial heterogeneity and macro-structures. The newer technologies are more challenging to be applied in a high throughput way due to the demands of downstream analysis and prohibitive cost.

Figure 2.. Common themes that emerge from precancer atlasing studies.

Through the multi-dimensional characterizations of precancerous lesions along the progression axis, a continuum of molecular and cellular alterations and increased heterogeneity were found. Many driver events can already be observed in premalignancies, implying their roles in tumor initiation, whereas less prevalent and more diverse sporadic alterations are their key players fueling progression. A cytotoxic immune environment usually presents in the precancers and is gradually replaced by an immunosuppressive environment. Atlasing efforts identify biomarkers and elucidate biological mechanisms in tumor progression that can potentially predict a precancer’s risk of progression. They can also provide valuable targets for cancer intervention and prevention. Abbreviations: NK- nature killer cell, TH: T Helper cell, CTL- cytotoxic T lymphocyte, M1&2- M1&M2 macrophages, mDC: mature dendritic cell, T-reg - regulatory T cell, MDSC- myeloid derived suppressor cell, iDC-immature dendritic cell.