Subtype-specific kinase dependency regulates growth and metastasis of poor-prognosis mesenchymal colorectal cancer.

Autor: Buikhuisen JY; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, location AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Gomez Barila PM; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, location AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Cameron K; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, location AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Suijkerbuijk SJE; Oncode Institute, Amsterdam, The Netherlands.; Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Lieftink C; Oncode Institute, Amsterdam, The Netherlands.; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands., di Franco S; Department of Surgical Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy., Krotenberg Garcia A; Oncode Institute, Amsterdam, The Netherlands.; Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Uceda Castro R; Oncode Institute, Amsterdam, The Netherlands.; Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Lenos KJ; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, location AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Nijman LE; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, location AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Torang A; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, location AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Longobardi C; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, location AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., de Jong JH; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, location AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Dekker D; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, location AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Stassi G; Department of Surgical Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy., Vermeulen L; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, location AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Beijersbergen RL; Oncode Institute, Amsterdam, The Netherlands.; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands., van Rheenen J; Oncode Institute, Amsterdam, The Netherlands.; Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Huveneers S; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands., Medema JP; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, location AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. j.p.medema@amsterdamumc.nl.; Oncode Institute, Amsterdam, The Netherlands. j.p.medema@amsterdamumc.nl.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2023 Mar 03; Vol. 42 (1), pp. 56. Date of Electronic Publication: 2023 Mar 03.
DOI: 10.1186/s13046-023-02600-9
Abstrakt: Background: Colorectal 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).
Methods: To 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.
Results: PAK2 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.
Conclusion: Our data reveal a unique dependency of mesenchymal CRC and provide a rationale for PAK2 inhibition to target this aggressive subgroup of colorectal cancer.
(© 2023. The Author(s).)
Databáze: MEDLINE
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