7 research outputs found
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 organoidsDKK3reduces the antitumor
effects of natural killer cells (NK cells). Altogether, our data provide
new insights into the role of SMAD4 perturbation in advanced CRC
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 organoidsDKK3reduces the antitumor
effects of natural killer cells (NK cells). Altogether, our data provide
new insights into the role of SMAD4 perturbation in advanced CRC
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 organoidsDKK3reduces the antitumor
effects of natural killer cells (NK cells). Altogether, our data provide
new insights into the role of SMAD4 perturbation in advanced CRC
Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma
More than half of patients with malignant mesothelioma show alterations in the BAP1 tumor-suppressor gene. Being a member of the Polycomb repressive deubiquitinating (PR-DUB) complex, BAP1 loss results in an altered epigenome, which may create new vulnerabilities that remain largely unknown. Here, we performed a CRISPR-Cas9 kinome screen in mesothelioma cells that identified two kinases in the mevalonate/cholesterol biosynthesis pathway. Furthermore, our analysis of chromatin, expression, and genetic perturbation data in mesothelioma cells suggests a dependency on PR complex 2 (PRC2)-mediated silencing. Pharmacological inhibition of PRC2 elevates the expression of cholesterol biosynthesis genes only in BAP1-deficient mesothelioma, thereby sensitizing these cells to the combined targeting of PRC2 and the mevalonate pathway. Finally, by subjecting autochthonous Bap1-deficient mesothelioma mice or xenografts to mevalonate pathway inhibition (zoledronic acid) and PRC2 inhibition (tazemetostat), we demonstrate a potent anti-tumor effect, suggesting a targeted combination therapy for Bap1-deficient mesothelioma
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 organoidsDKK3reduces the antitumor
effects of natural killer cells (NK cells). Altogether, our data provide
new insights into the role of SMAD4 perturbation in advanced CRC