Recent molecular classifications of colorectal cancer (CRC) based on global gene expression profi... more Recent molecular classifications of colorectal cancer (CRC) based on global gene expression profiles have defined subtypes
displaying resistance to therapy and poor prognosis. Upon evaluation of these classification systems, we discovered that
their predictive power arises from genes expressed by stromal cells rather than epithelial tumor cells. Bioinformatic and
immunohistochemical analyses identify stromal markers that associate robustly with disease relapse across the various
classifications. Functional studies indicate that cancer-associated fibroblasts (CAFs) increase the frequency of tumor-initiating
cells, an effect that is dramatically enhanced by transforming growth factor (TGF)-b signaling. Likewise, we find that all poorprognosis
CRC subtypes share a gene program induced by TGF-b in tumor stromal cells. Using patient-derived tumor organoids
and xenografts, we show that the use of TGF-b signaling inhibitors to block the cross-talk between cancer cells and the
microenvironment halts disease progression.
A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-b path... more A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-b pathway, yet, paradoxically, they are characterized by elevated TGF-b production. Here, we unveil a prometastatic program induced by TGF-b in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-b on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-b-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-b stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC.
Recent molecular classifications of colorectal cancer (CRC) based on global gene expression profi... more Recent molecular classifications of colorectal cancer (CRC) based on global gene expression profiles have defined subtypes
displaying resistance to therapy and poor prognosis. Upon evaluation of these classification systems, we discovered that
their predictive power arises from genes expressed by stromal cells rather than epithelial tumor cells. Bioinformatic and
immunohistochemical analyses identify stromal markers that associate robustly with disease relapse across the various
classifications. Functional studies indicate that cancer-associated fibroblasts (CAFs) increase the frequency of tumor-initiating
cells, an effect that is dramatically enhanced by transforming growth factor (TGF)-b signaling. Likewise, we find that all poorprognosis
CRC subtypes share a gene program induced by TGF-b in tumor stromal cells. Using patient-derived tumor organoids
and xenografts, we show that the use of TGF-b signaling inhibitors to block the cross-talk between cancer cells and the
microenvironment halts disease progression.
A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-b path... more A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-b pathway, yet, paradoxically, they are characterized by elevated TGF-b production. Here, we unveil a prometastatic program induced by TGF-b in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-b on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-b-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-b stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC.
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Papers by Antoni Riera
displaying resistance to therapy and poor prognosis. Upon evaluation of these classification systems, we discovered that
their predictive power arises from genes expressed by stromal cells rather than epithelial tumor cells. Bioinformatic and
immunohistochemical analyses identify stromal markers that associate robustly with disease relapse across the various
classifications. Functional studies indicate that cancer-associated fibroblasts (CAFs) increase the frequency of tumor-initiating
cells, an effect that is dramatically enhanced by transforming growth factor (TGF)-b signaling. Likewise, we find that all poorprognosis
CRC subtypes share a gene program induced by TGF-b in tumor stromal cells. Using patient-derived tumor organoids
and xenografts, we show that the use of TGF-b signaling inhibitors to block the cross-talk between cancer cells and the
microenvironment halts disease progression.
displaying resistance to therapy and poor prognosis. Upon evaluation of these classification systems, we discovered that
their predictive power arises from genes expressed by stromal cells rather than epithelial tumor cells. Bioinformatic and
immunohistochemical analyses identify stromal markers that associate robustly with disease relapse across the various
classifications. Functional studies indicate that cancer-associated fibroblasts (CAFs) increase the frequency of tumor-initiating
cells, an effect that is dramatically enhanced by transforming growth factor (TGF)-b signaling. Likewise, we find that all poorprognosis
CRC subtypes share a gene program induced by TGF-b in tumor stromal cells. Using patient-derived tumor organoids
and xenografts, we show that the use of TGF-b signaling inhibitors to block the cross-talk between cancer cells and the
microenvironment halts disease progression.