Page 35 - SDIR5 Abstract book 21 12 2021.

IMAGING IN CANCER

Defining and imaging colon cancer heterogeneity

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1
2
Jelena Stanisavljević , Clara Morral , Xavier Hernando-Momblona , Eduard Batlle 2, 3
1 ICFO-Institut de Ciencies Fotoniques, The Barcelona Institute of Science and Technology (BIST), Spain
2 Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST)
3 ICREA, Barcelona, Spain

LGR5 (Leucine-rich repeat-containing G protein-coupled receptor) has been widely used as the marker of
cancer stem cells (CSCs) in colorectal cancers (CRCs). However, lineage-tracing studies suggest that only a
small portion of the LGR5 pool gives rise to large clones, and recent studies have shown LGR5 negative cells
present in primary CRCs act as seeds for metastasis.
We have combined patient-derived organoids, several CRISPR-based techniques, single-cell sequencing
analysis, and click-chemistry-based labeling to describe a previously unappreciated heterogeneity in the
biosynthetic capacities of CRC cells. In transplantation experiments and intact tumors, most of the
ribosomal DNA transcription and protein synthesis in CRCs occurs in a limited subset of tumor cells, and
both LGR5+ and LGR5− tumor cells that display elevated biosynthetic features function as CSCs. Cancer
cells within the biosynthetic domains are characterized by elevated levels of the RNA polymerase I subunit
A (POLR1A). Genetic ablation of POLR1A-high cell population imposes an irreversible growth arrest on CRCs.
We show that elevated biosynthesis defines stemness in both LGR5+ and LGR5- tumor cells. Some
differentiated (KRT20+) cells can give rise to progeny, but as differentiation and the shutdown of the rDNA
machinery progresses, the capacity to return to the previous state is gradually lost. Therefore, a common
architecture in CRCs is a simple cell hierarchy based on the differential capacity to transcribe ribosomal
DNA and synthesize proteins. Our findings fit well with a model where the properties of cancer cells are
defined both by the microenvironment and cell-intrinsic programs dictated by a stem cell hierarchy.

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