Receptor tyrosine kinase signaling and extracellular matrix cues in ovarian cancer metastasis and drug resistance
Author: Moyano Galceran, Lidia
Date: 2021-09-03
Location: Lecture Hall Inghesalen, Tomtebodavägen 18a, Karolinska Institutet, Solna
Time: 14.00
Department: Inst för mikrobiologi, tumör- och cellbiologi / Dept of Microbiology, Tumor and Cell Biology
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Thesis (3.096Mb)
Abstract
Albeit many studies have contributed towards understanding the origin, development, treatment response and evolution of high-grade serous ovarian carcinoma (HGSC), the exact supporting mechanisms are still not fully understood, and the disease remains a clinical challenge with low 5-year survival and high recurrence rate. The purpose of this thesis was to study the dynamic communication between the cancer cells and the tumor microenvironment (TME) to understand how these influence and are affected by disease progression and chemotherapy in the context of HGSC.
In Paper I we uncovered a robust platinum chemotherapy-induced ERK1/2-RSK1/2-EphA2- GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, RSK inhibition halted this signaling switch and even restored the canonical, tumor-suppressive EphA2 signaling, resulting in the efficient sensitization of HGSC cells to platinum treatment in vitro and in vivo. In addition, we described GPRC5A association to chemotherapy response, overall and progression-free survival in HGSC patients. In Paper II we reported that the ligand ephrinA5 was highly expressed in the most aggressive ovarian cancer type (i.e. HGSC) and further upregulated both at the protein and mRNA levels upon disease progression. Functionally, ephrinA5 left unaffected or even impaired EphA2 tumorsuppressive signaling. In Paper III we characterized the matrisome of HGSC solid tumors (primary and different metastatic sites) and ascites, pre- and post-chemotherapy. We showed that extracellular matrix (ECM) stiffness promoted cell proliferation and spreading (via focal adhesion kinase and YAP/TAZ signaling), and protected HGSC cells against cisplatinmediated, apoptosis-inducing DNA damage. In addition, we reported that different ECM components altered cell adhesion, migration and chemoresistance in diverse ways. In particular, collagen VI enhanced the chemoresistance of disease-recurrent, patient-derived organoids, was upregulated in HGSC patients upon chemotherapy and associated to poor survival.
In conclusion, the findings of this thesis help us to better understand how ovarian cancer cells activate specific signaling mechanisms and engage in altered ECM remodeling and TME interactions that enhance cancer cell growth, metastatic and chemoresistance capabilities.
In Paper I we uncovered a robust platinum chemotherapy-induced ERK1/2-RSK1/2-EphA2- GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, RSK inhibition halted this signaling switch and even restored the canonical, tumor-suppressive EphA2 signaling, resulting in the efficient sensitization of HGSC cells to platinum treatment in vitro and in vivo. In addition, we described GPRC5A association to chemotherapy response, overall and progression-free survival in HGSC patients. In Paper II we reported that the ligand ephrinA5 was highly expressed in the most aggressive ovarian cancer type (i.e. HGSC) and further upregulated both at the protein and mRNA levels upon disease progression. Functionally, ephrinA5 left unaffected or even impaired EphA2 tumorsuppressive signaling. In Paper III we characterized the matrisome of HGSC solid tumors (primary and different metastatic sites) and ascites, pre- and post-chemotherapy. We showed that extracellular matrix (ECM) stiffness promoted cell proliferation and spreading (via focal adhesion kinase and YAP/TAZ signaling), and protected HGSC cells against cisplatinmediated, apoptosis-inducing DNA damage. In addition, we reported that different ECM components altered cell adhesion, migration and chemoresistance in diverse ways. In particular, collagen VI enhanced the chemoresistance of disease-recurrent, patient-derived organoids, was upregulated in HGSC patients upon chemotherapy and associated to poor survival.
In conclusion, the findings of this thesis help us to better understand how ovarian cancer cells activate specific signaling mechanisms and engage in altered ECM remodeling and TME interactions that enhance cancer cell growth, metastatic and chemoresistance capabilities.
List of papers:
I. Moyano-Galceran L, Pietilä EA*, Turunen SP*, Corvigno S, Hjerpe E, Bulanova D, Joneborg U, Alkasalias T, Miki Y, Yashiro M, Chernenko A, Jukonen J, Singh M, Dahlstrand H, Carlson JW, Lehti K. Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer. EMBO Molecular Medicine. 2020 Apr 7;12(4):e11177. *Equal contribution.
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II. Jukonen J, Moyano-Galceran L*, Höpfner K*, Pietilä EA, Lehtinen L, Huhtinen K, Gucciardo E, Hynninen J, Hietanen S, Grénman S, Ojala PM, Carpén O, Lehti K. Aggressive and recurrent ovarian cancers upregulate ephrinA5, a noncanonical effector of EphA2 signaling duality. Scientific Reports. 2021 Apr 23;11(1):8856. *Equal contribution.
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III. Pietilä EA, Gonzalez-Molina J, Moyano-Galceran L, Jamalzadeh S, Zhang K, Lehtinen L, Turunen SP, Martins T, Gultekin O, Lamminen T, Kaipio K, Joneborg U, Hynninen J, Hietanen S, Grénman S, Lehtonen R, Hautaniemi S, Carpén O, Carlson JW, Lehti K. Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance. Nature Communications. 2021 Jun 23;12(1):3904.
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I. Moyano-Galceran L, Pietilä EA*, Turunen SP*, Corvigno S, Hjerpe E, Bulanova D, Joneborg U, Alkasalias T, Miki Y, Yashiro M, Chernenko A, Jukonen J, Singh M, Dahlstrand H, Carlson JW, Lehti K. Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer. EMBO Molecular Medicine. 2020 Apr 7;12(4):e11177. *Equal contribution.
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II. Jukonen J, Moyano-Galceran L*, Höpfner K*, Pietilä EA, Lehtinen L, Huhtinen K, Gucciardo E, Hynninen J, Hietanen S, Grénman S, Ojala PM, Carpén O, Lehti K. Aggressive and recurrent ovarian cancers upregulate ephrinA5, a noncanonical effector of EphA2 signaling duality. Scientific Reports. 2021 Apr 23;11(1):8856. *Equal contribution.
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III. Pietilä EA, Gonzalez-Molina J, Moyano-Galceran L, Jamalzadeh S, Zhang K, Lehtinen L, Turunen SP, Martins T, Gultekin O, Lamminen T, Kaipio K, Joneborg U, Hynninen J, Hietanen S, Grénman S, Lehtonen R, Hautaniemi S, Carpén O, Carlson JW, Lehti K. Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance. Nature Communications. 2021 Jun 23;12(1):3904.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Lehti, Kaisa
Co-supervisor: Carlson, Joseph; Turunen, Pauliina
Issue date: 2021-08-09
Rights:
Publication year: 2021
ISBN: 978-91-8016-246-3
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