Distinct Transcriptional Programs in Ascitic and Solid Cancer Cells Induce Different Responses to Chemotherapy in High-Grade Serous Ovarian Cancer

Nele Loret; Niels Vandamme; Jordy De Coninck; Joachim Taminau; Kato De Clercq; Gillian Blancke; Sven Jonckheere; Steven Goossens; Kelly Lemeire; Sofie De Prijck; Kevin Verstaen; Ruth Seurinck; Jo Van Dorpe; Steven Weyers; Hannelore Denys; Koen Van de Vijver; Bart N. Lambrecht; Philippe Tummers; Yvan Saeys; Geert Berx

doi:10.1158/1541-7786.MCR-21-0565

Distinct Transcriptional Programs in Ascitic and Solid Cancer Cells Induce Different Responses to Chemotherapy in High-Grade Serous Ovarian Cancer

Nele Loret, Niels Vandamme, Jordy De Coninck, Joachim Taminau, Kato De Clercq, Gillian Blancke, Sven Jonckheere, Steven Goossens, Kelly Lemeire, Sofie De Prijck, Kevin Verstaen, Ruth Seurinck, Jo Van Dorpe, Steven Weyers, Hannelore Denys, Koen Van de Vijver, Bart N. Lambrecht, Philippe Tummers, Yvan Saeys, Geert Berx

Pulmonary Medicine

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

High-grade serous ovarian cancer (HGSOC) is responsible for the largest number of ovarian cancer deaths. The frequent therapy-resistant relapses necessitate a better understanding of mechanisms driving therapy resistance. Therefore, we mapped more than a hundred thousand cells of HGSOC patients in different phases of the disease, using single-cell RNA sequencing. Within patients, we compared chemonaive with chemotreated samples. As such, we were able to create a single-cell atlas of different HGSOC lesions and their treatment. This revealed a high intrapatient concordance between spatially distinct metastases. In addition, we found remarkable baseline differences in transcriptomics of ascitic and solid cancer cells, resulting in a different response to chemotherapy. Moreover, we discovered different robust subtypes of cancer-associated fibroblasts (CAF) in all patients. Besides inflammatory CAFs, vascular CAFs, and matrix CAFs, we identified a new CAF subtype that was characterized by high expression of STAR, TSPAN8, and ALDH1A1 and clearly enriched after chemotherapy. Together, tumor heterogeneity in both cancer and stromal cells contributes to therapy resistance in HGSOC and could form the basis of novel therapeutic strategies that differentiate between ascitic and solid disease.

Original language	English
Pages (from-to)	1532-1547
Number of pages	16
Journal	Molecular cancer research : MCR
Volume	20
Issue number	10
DOIs	https://doi.org/10.1158/1541-7786.MCR-21-0565
Publication status	Published - 4 Oct 2022

Bibliographical note

Funding Information:
R. Seurinck reports grants from Flanders AI Research Program during the conduct of the study. H. Denys reports nonfinancial support and other support from Pfizer, Roche, Pharmamar, AstraZeneca, Novartis, GSK, Amgen, Teva, Seagen, and MSD outside the submitted work. No disclosures were reported by the other authors.

Funding Information:
N. Loret was supported by a personal PhD BOF fellowship from Ghent University (2016–2021). G. Berx’s laboratory is supported by the Strategic Basic Research (SBO; S008518N), the Geconcerteerde Onderzoeksacties Ghent University (GOA22-21 BOF), Stichting tegen Kanker (F/2020/1437 and C/2020/1436), and Kom Op Tegen Kanker (ref. 000081351).

Publisher Copyright:
©2022 American Association for Cancer Research.

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10.1158/1541-7786.MCR-21-0565

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Loret, N., Vandamme, N., De Coninck, J., Taminau, J., De Clercq, K., Blancke, G., Jonckheere, S., Goossens, S., Lemeire, K., De Prijck, S., Verstaen, K., Seurinck, R., Van Dorpe, J., Weyers, S., Denys, H., Van de Vijver, K., Lambrecht, B. N., Tummers, P., Saeys, Y., & Berx, G. (2022). Distinct Transcriptional Programs in Ascitic and Solid Cancer Cells Induce Different Responses to Chemotherapy in High-Grade Serous Ovarian Cancer. Molecular cancer research : MCR, 20(10), 1532-1547. https://doi.org/10.1158/1541-7786.MCR-21-0565

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title = "Distinct Transcriptional Programs in Ascitic and Solid Cancer Cells Induce Different Responses to Chemotherapy in High-Grade Serous Ovarian Cancer",

abstract = "High-grade serous ovarian cancer (HGSOC) is responsible for the largest number of ovarian cancer deaths. The frequent therapy-resistant relapses necessitate a better understanding of mechanisms driving therapy resistance. Therefore, we mapped more than a hundred thousand cells of HGSOC patients in different phases of the disease, using single-cell RNA sequencing. Within patients, we compared chemonaive with chemotreated samples. As such, we were able to create a single-cell atlas of different HGSOC lesions and their treatment. This revealed a high intrapatient concordance between spatially distinct metastases. In addition, we found remarkable baseline differences in transcriptomics of ascitic and solid cancer cells, resulting in a different response to chemotherapy. Moreover, we discovered different robust subtypes of cancer-associated fibroblasts (CAF) in all patients. Besides inflammatory CAFs, vascular CAFs, and matrix CAFs, we identified a new CAF subtype that was characterized by high expression of STAR, TSPAN8, and ALDH1A1 and clearly enriched after chemotherapy. Together, tumor heterogeneity in both cancer and stromal cells contributes to therapy resistance in HGSOC and could form the basis of novel therapeutic strategies that differentiate between ascitic and solid disease.",

author = "Nele Loret and Niels Vandamme and {De Coninck}, Jordy and Joachim Taminau and {De Clercq}, Kato and Gillian Blancke and Sven Jonckheere and Steven Goossens and Kelly Lemeire and {De Prijck}, Sofie and Kevin Verstaen and Ruth Seurinck and {Van Dorpe}, Jo and Steven Weyers and Hannelore Denys and {Van de Vijver}, Koen and Lambrecht, {Bart N.} and Philippe Tummers and Yvan Saeys and Geert Berx",

note = "Funding Information: R. Seurinck reports grants from Flanders AI Research Program during the conduct of the study. H. Denys reports nonfinancial support and other support from Pfizer, Roche, Pharmamar, AstraZeneca, Novartis, GSK, Amgen, Teva, Seagen, and MSD outside the submitted work. No disclosures were reported by the other authors. Funding Information: N. Loret was supported by a personal PhD BOF fellowship from Ghent University (2016–2021). G. Berx{\textquoteright}s laboratory is supported by the Strategic Basic Research (SBO; S008518N), the Geconcerteerde Onderzoeksacties Ghent University (GOA22-21 BOF), Stichting tegen Kanker (F/2020/1437 and C/2020/1436), and Kom Op Tegen Kanker (ref. 000081351). Publisher Copyright: {\textcopyright}2022 American Association for Cancer Research.",

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doi = "10.1158/1541-7786.MCR-21-0565",

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Loret, N, Vandamme, N, De Coninck, J, Taminau, J, De Clercq, K, Blancke, G, Jonckheere, S, Goossens, S, Lemeire, K, De Prijck, S, Verstaen, K, Seurinck, R, Van Dorpe, J, Weyers, S, Denys, H, Van de Vijver, K, Lambrecht, BN, Tummers, P, Saeys, Y & Berx, G 2022, 'Distinct Transcriptional Programs in Ascitic and Solid Cancer Cells Induce Different Responses to Chemotherapy in High-Grade Serous Ovarian Cancer', Molecular cancer research : MCR, vol. 20, no. 10, pp. 1532-1547. https://doi.org/10.1158/1541-7786.MCR-21-0565

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T1 - Distinct Transcriptional Programs in Ascitic and Solid Cancer Cells Induce Different Responses to Chemotherapy in High-Grade Serous Ovarian Cancer

AU - Loret, Nele

AU - Vandamme, Niels

AU - De Coninck, Jordy

AU - Taminau, Joachim

AU - De Clercq, Kato

AU - Blancke, Gillian

AU - Jonckheere, Sven

AU - Goossens, Steven

AU - Lemeire, Kelly

AU - De Prijck, Sofie

AU - Verstaen, Kevin

AU - Seurinck, Ruth

AU - Van Dorpe, Jo

AU - Weyers, Steven

AU - Denys, Hannelore

AU - Van de Vijver, Koen

AU - Lambrecht, Bart N.

AU - Tummers, Philippe

AU - Saeys, Yvan

AU - Berx, Geert

N1 - Funding Information: R. Seurinck reports grants from Flanders AI Research Program during the conduct of the study. H. Denys reports nonfinancial support and other support from Pfizer, Roche, Pharmamar, AstraZeneca, Novartis, GSK, Amgen, Teva, Seagen, and MSD outside the submitted work. No disclosures were reported by the other authors. Funding Information: N. Loret was supported by a personal PhD BOF fellowship from Ghent University (2016–2021). G. Berx’s laboratory is supported by the Strategic Basic Research (SBO; S008518N), the Geconcerteerde Onderzoeksacties Ghent University (GOA22-21 BOF), Stichting tegen Kanker (F/2020/1437 and C/2020/1436), and Kom Op Tegen Kanker (ref. 000081351). Publisher Copyright: ©2022 American Association for Cancer Research.

PY - 2022/10/4

Y1 - 2022/10/4

N2 - High-grade serous ovarian cancer (HGSOC) is responsible for the largest number of ovarian cancer deaths. The frequent therapy-resistant relapses necessitate a better understanding of mechanisms driving therapy resistance. Therefore, we mapped more than a hundred thousand cells of HGSOC patients in different phases of the disease, using single-cell RNA sequencing. Within patients, we compared chemonaive with chemotreated samples. As such, we were able to create a single-cell atlas of different HGSOC lesions and their treatment. This revealed a high intrapatient concordance between spatially distinct metastases. In addition, we found remarkable baseline differences in transcriptomics of ascitic and solid cancer cells, resulting in a different response to chemotherapy. Moreover, we discovered different robust subtypes of cancer-associated fibroblasts (CAF) in all patients. Besides inflammatory CAFs, vascular CAFs, and matrix CAFs, we identified a new CAF subtype that was characterized by high expression of STAR, TSPAN8, and ALDH1A1 and clearly enriched after chemotherapy. Together, tumor heterogeneity in both cancer and stromal cells contributes to therapy resistance in HGSOC and could form the basis of novel therapeutic strategies that differentiate between ascitic and solid disease.

AB - High-grade serous ovarian cancer (HGSOC) is responsible for the largest number of ovarian cancer deaths. The frequent therapy-resistant relapses necessitate a better understanding of mechanisms driving therapy resistance. Therefore, we mapped more than a hundred thousand cells of HGSOC patients in different phases of the disease, using single-cell RNA sequencing. Within patients, we compared chemonaive with chemotreated samples. As such, we were able to create a single-cell atlas of different HGSOC lesions and their treatment. This revealed a high intrapatient concordance between spatially distinct metastases. In addition, we found remarkable baseline differences in transcriptomics of ascitic and solid cancer cells, resulting in a different response to chemotherapy. Moreover, we discovered different robust subtypes of cancer-associated fibroblasts (CAF) in all patients. Besides inflammatory CAFs, vascular CAFs, and matrix CAFs, we identified a new CAF subtype that was characterized by high expression of STAR, TSPAN8, and ALDH1A1 and clearly enriched after chemotherapy. Together, tumor heterogeneity in both cancer and stromal cells contributes to therapy resistance in HGSOC and could form the basis of novel therapeutic strategies that differentiate between ascitic and solid disease.

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U2 - 10.1158/1541-7786.MCR-21-0565

DO - 10.1158/1541-7786.MCR-21-0565

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SN - 1541-7786

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ER -

Distinct Transcriptional Programs in Ascitic and Solid Cancer Cells Induce Different Responses to Chemotherapy in High-Grade Serous Ovarian Cancer

Abstract

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