Comparative Study of Organoids from Patient-Derived Normal and Tumor Colon and Rectal Tissue

Abstract

Colon and rectal tumors, often referred to as colorectal cancer, show different gene expression patterns in studies that analyze whole tissue biopsies containing a mix of tumor and non-tumor cells. To better characterize colon and rectal tumors, we investigated the gene expression profile of organoids generated from endoscopic biopsies of rectal tumors and adjacent normal colon and rectum mucosa from therapy-naive rectal cancer patients. We also studied the effect of vitamin D on these organoid types. Gene profiling was performed by RNA-sequencing. Organoids from a normal colon and rectum had a shared gene expression profile that profoundly differed from that of rectal tumor organoids. We identified a group of genes of the biosynthetic machinery as rectal tumor organoid-specific, including those encoding the RNA polymerase II subunits POLR2H and POLR2J. The active vitamin D metabolite 1α,25-dihydroxyvitamin D3/calcitriol upregulated stemness-related genes (LGR5, LRIG1, SMOC2, and MSI1) in normal rectum organoids, while it downregulated differentiation marker genes (TFF2 and MUC2). Normal colon and rectum organoids share similar gene expression patterns and respond similarly to calcitriol. Rectal tumor organoids display distinct and heterogeneous gene expression profiles, with differences with respect to those of colon tumor organoids, and respond differently to calcitriol than normal rectum organoids.

Organoids and Colorectal Cancer

“…However, a group of genes of the biosynthetic machinery were found as rectal tumor organoid-specific, including those encoding the RNA polymerase II subunits POLR2H and POLR2J. This agrees with the clinical differences between colon and rectal cancers [ 94 ].…”

“…Our group has used organoid technology to identify possible differences between colon and rectum tumors. We compared by RNA-seq assays the transcriptomic profiles of normal and tumor PDOs from colon (sigmoid) and rectum [ 94 ]. We observed that organoids from both origins shared a similar gene expression profile.…”

Immune Response: A Missed Opportunity Between Vitamin D and Radiotherapy

“…On the one hand, 1,25(OH) 2 D 3 can induce cell differentiation in colon tumor organoids and lead to a more epithelial phenotype (Fernandez-Barral et al, 2020b). On the other hand, 1,25(OH) 2 D 3 upregulates stemness-related genes and downregulates differentiation genes in normal rectum organoids (Costales-Carrera et al, 2020). These results demonstrate the different roles of vitamin D in normal stem cells and colon CSCs.…”

A breast cancer patient-derived xenograft and organoid platform for drug discovery and precision oncology

“…Evidence is accumulating to indicate that patient-derived organoids (PDO) show strong biological concordance with the tumors from which they are derived. Pancreatic and colorectal tumors, in particular, have been extensively modeled using patient-derived organoids [6][7] . Using whole genome analysis, Gendoo et al reported good concordance between patient tumors, PDX, and PDO in pancreatic cancer 8 .…”