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bioRxiv : the preprint server for biology2024; 2024.09.25.615007; doi: 10.1101/2024.09.25.615007

Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma.

Abstract: High-Grade Serous Ovarian Cancer (HGSOC) originates from fallopian tube (FT) precursors. However, the molecular changes that occur as precancerous lesions progress to HGSOC are not well understood. To address this, we integrated high-plex imaging and spatial transcriptomics to analyze human tissue samples at different stages of HGSOC development, including p53 signatures, serous tubal intraepithelial carcinomas (STIC), and invasive HGSOC. Our findings reveal immune modulating mechanisms within precursor epithelium, characterized by chromosomal instability, persistent interferon (IFN) signaling, and dysregulated innate and adaptive immunity. FT precursors display elevated expression of MHC-class I, including HLA-E, and IFN-stimulated genes, typically linked to later-stage tumorigenesis. These molecular alterations coincide with progressive shifts in the tumor microenvironment, transitioning from immune surveillance in early STICs to immune suppression in advanced STICs and cancer. These insights identify potential biomarkers and therapeutic targets for HGSOC interception and clarify the molecular transitions from precancer to cancer.
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Publication Date: 2024-09-27 PubMed ID: 39386723PubMed Central: PMC11463462DOI: 10.1101/2024.09.25.615007Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research explores the molecular changes that take place as precancerous lesions in the fallopian tube advance to High-Grade Serous Ovarian Cancer (HGSOC). The study identifies immune modulating mechanisms, chromosomal instability, and dysregulation of innate immunity as some factors that influence this progression.

Integration of High-Plex Imaging and Spatial Transcriptomics

  • The researchers coupled high-plex imaging with spatial transcriptomics, disciplines that allow for the visualization and analysis of biological tissues at the molecular level. High-plex imaging is a type of microscopy that can identify and measure multiple biomolecules in a single sample, while spatial transcriptomics studies the distribution and concentration of RNA molecules in tissue sections. By integrating these techniques, they were able to investigate the alterations within cells and their surrounding environment during the different stages of HGSOC development.

Detecting Molecular Changes in Precursors to HGSOC

  • The team studied samples from various stages of the disease’s development, focusing on p53 signatures, serous tubal intraepithelial carcinomas (STICs) and invasive HGSOC. p53 signatures and STICs are precursors to HGSOC, serving as molecular markers for early recognition of potential high-grade ovarian cancers.
  • Their investigations uncovered immune modulating mechanisms within the precursor epithelium. These included chromosomal instability, persistent interferon (IFN) signaling, and dysregulated innate and adaptive immunity. All these factors can promote the progression of precancerous lesions to HGSOC.

Update on Tumor Microenvironment and Immune Surveillance

  • The study discovered a correlation between molecular alterations and shifts in the tumor microenvironment. The environment transitions from a state of immune surveillance in the early stages of STICs to a state of immune suppression in advanced STICs and cancer.
  • They found increased expression of MHC-class I, including HLA-E, and IFN-stimulated genes within the precursors, signifying a link to later-stage tumorigenesis.

Implications for Future Research and Treatment

  • The findings from the study can help identify potential biomarkers for HGSOC, potentially aiding in early detection and intervention of the disease. Moreover, the molecular changes highlighted can serve as therapeutic targets, creating a path for more personalized and effective treatments to be developed for HGSOC.

Cite This Article

APA
Kader T, Lin JR, Hug C, Coy S, Chen YA, de Bruijn I, Shih N, Jung E, Pelletier RJ, Leon ML, Mingo G, Omran DK, Lee JS, Yapp C, Satravada BA, Kundra R, Xu Y, Chan S, Tefft JB, Muhlich J, Kim S, Gysler SM, Agudo J, Heath JR, Schultz N, Drescher C, Sorger PK, Drapkin R, Santagata S. (2024). Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma. bioRxiv, 2024.09.25.615007. https://doi.org/10.1101/2024.09.25.615007

Publication

bioRxiv : the preprint server for biology
ISSN: 2692-8205
NlmUniqueID: 101680187
Country: United States
Language: English
PII: 2024.09.25.615007

Researcher Affiliations

Kader, Tanjina
  • Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Ludwig Center at Harvard, Boston, MA, USA.
Lin, Jia-Ren
  • Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Ludwig Center at Harvard, Boston, MA, USA.
Hug, Clemens
  • Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
Coy, Shannon
  • Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Ludwig Center at Harvard, Boston, MA, USA.
  • Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Chen, Yu-An
  • Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Ludwig Center at Harvard, Boston, MA, USA.
de Bruijn, Ino
  • Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA.
Shih, Natalie
  • Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Jung, Euihye
  • Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Pelletier, Roxanne J
  • Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
Leon, Mariana Lopez
  • Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
Mingo, Gabriel
  • Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Omran, Dalia Khaled
  • Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Lee, Jong Suk
  • Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Ludwig Center at Harvard, Boston, MA, USA.
Yapp, Clarence
  • Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Ludwig Center at Harvard, Boston, MA, USA.
Satravada, Baby Anusha
  • Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA.
Kundra, Ritika
  • Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA.
Xu, Yilin
  • Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Ludwig Center at Harvard, Boston, MA, USA.
  • Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Chan, Sabrina
  • Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Ludwig Center at Harvard, Boston, MA, USA.
Tefft, Juliann B
  • Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
Muhlich, Jeremy
  • Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
Kim, Sarah
  • Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Gysler, Stefan M
  • Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Agudo, Judith
  • Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
Heath, James R
  • Institute of Systems Biology, Seattle, WA, USA.
  • Department of Bioengineering, University of Washington, Seattle, WA, USA.
Schultz, Nikolaus
  • Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA.
Drescher, Charles
  • Swedish Cancer Institute Gynecologic Oncology and Pelvic Surgery, Seattle, WA, USA.
Sorger, Peter K
  • Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Ludwig Center at Harvard, Boston, MA, USA.
  • Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
Drapkin, Ronny
  • Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Santagata, Sandro
  • Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Ludwig Center at Harvard, Boston, MA, USA.
  • Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Department of Systems Biology, Harvard Medical School, Boston, MA, USA.

Grant Funding

  • P50 CA228991 / NCI NIH HHS
  • U2C CA233262 / NCI NIH HHS

Conflict of Interest Statement

DECLARATION OF INTERESTS PKS is a co-founder and member of the BOD of Glencoe Software and member of the SAB for RareCyte, NanoString, and Montai Health; he holds equity in Glencoe and RareCyte. PKS is a consultant for Merck. RD is a member of the SAB for Repare Therapeutics and is a consultant for Light Horse Therapeutics and Abbvie. The other authors declare no outside interests.

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