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Dependency of colorectal cancer on a TGF-?-driven program in stromal cells for metastasis initiation.

ABSTRACT: A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-? pathway, yet, paradoxically, they are characterized by elevated TGF-? production. Here, we unveil a prometastatic program induced by TGF-? in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-? 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-?-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-? stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC.

SUBMITTER: Calon A

PROVIDER: S-EPMC3512565 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation.

Calon Alexandre A Espinet Elisa E Palomo-Ponce Sergio S Tauriello Daniele V F DV Iglesias Mar M Céspedes María Virtudes MV Sevillano Marta M Nadal Cristina C Jung Peter P Zhang Xiang H-F XH Byrom Daniel D Riera Antoni A Rossell David D Mangues Ramón R Massagué Joan J Sancho Elena E Batlle Eduard E

Cancer cell 20121101 5

A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-β pathway, yet, paradoxically, they are characterized by elevated TGF-β production. Here, we unveil a prometastatic program induced by TGF-β in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-β on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to ...[more]

PMID: 23153532

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Project description:BackgroundColorectal cancer (CRC) can be divided into four consensus molecular subtypes (CMS), each with distinct biological features. CMS4 is associated with epithelial-mesenchymal transition and stromal infiltration (Guinney et al., Nat Med 21:1350-6, 2015; Linnekamp et al., Cell Death Differ 25:616-33, 2018), whereas clinically it is characterized by lower responses to adjuvant therapy, higher incidence of metastatic spreading and hence dismal prognosis (Buikhuisen et al., Oncogenesis 9:66, 2020).MethodsTo understand the biology of the mesenchymal subtype and unveil specific vulnerabilities, a large CRISPR-Cas9 drop-out screen was performed on 14 subtyped CRC cell lines to uncover essential kinases in all CMSs. Dependency of CMS4 cells on p21-activated kinase 2 (PAK2) was validated in independent 2D and 3D in vitro cultures and in vivo models assessing primary and metastatic outgrowth in liver and peritoneum. TIRF microscopy was used to uncover actin cytoskeleton dynamics and focal adhesion localization upon PAK2 loss. Subsequent functional assays were performed to determine altered growth and invasion patterns.ResultsPAK2 was identified as a key kinase uniquely required for growth of the mesenchymal subtype CMS4, both in vitro and in vivo. PAK2 plays an important role in cellular attachment and cytoskeletal rearrangements (Coniglio et al., Mol Cell Biol 28:4162-72, 2008; Grebenova et al., Sci Rep 9:17171, 2019). In agreement, deletion or inhibition of PAK2 impaired actin cytoskeleton dynamics in CMS4 cells and, as a consequence, significantly reduced invasive capacity, while it was dispensable for CMS2 cells. Clinical relevance of these findings was supported by the observation that deletion of PAK2 from CMS4 cells prevented metastatic spreading in vivo. Moreover, growth in a model for peritoneal metastasis was hampered when CMS4 tumor cells were deficient for PAK2.ConclusionOur data reveal a unique dependency of mesenchymal CRC and provide a rationale for PAK2 inhibition to target this aggressive subgroup of colorectal cancer.

Dataset Information

Dependency of colorectal cancer on a TGF-?-driven program in stromal cells for metastasis initiation.

Publications

Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation.

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