Multiomics of Colorectal Cancer Organoids Reveals Putative Mediators of Cancer Progression Resulting from SMAD4 Inactivation

The development of metastasis severely reduces the life
expectancy
of patients with colorectal cancer (CRC). Although loss of SMAD4 is
a key event in CRC progression, the resulting changes in biological
processes in advanced disease and metastasis are not fully understood.
Here, we applied a multiomics approach to a CRC organoid model that
faithfully reflects the metastasis-supporting effects of SMAD4 inactivation.
We show that loss of SMAD4 results in decreased differentiation and
activation of pro-migratory and cell proliferation processes, which
is accompanied by the disruption of several key oncogenic pathways,
including the TGFβ, WNT, and VEGF pathways. In addition, SMAD4
inactivation leads to increased secretion of proteins that are known
to be involved in a variety of pro-metastatic processes. Finally,
we show that one of the factors that is specifically secreted by SMAD4-mutant organoidsDKK3reduces the antitumor
effects of natural killer cells (NK cells). Altogether, our data provide
new insights into the role of SMAD4 perturbation in advanced CRC.