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Spatially resolved analysis of pancreatic cancer identifies therapy-associated remodeling of the tumor microenvironment.
Shiau, Carina; Cao, Jingyi; Gong, Dennis; Gregory, Mark T; Caldwell, Nicholas J; Yin, Xunqin; Cho, Jae-Won; Wang, Peter L; Su, Jennifer; Wang, Steven; Reeves, Jason W; Kim, Tae Kyung; Kim, Youngmi; Guo, Jimmy A; Lester, Nicole A; Bae, Jung Woo; Zhao, Ryan; Schurman, Nathan; Barth, Jamie L; Ganci, Maria L; Weissleder, Ralph; Jacks, Tyler; Qadan, Motaz; Hong, Theodore S; Wo, Jennifer Y; Roberts, Hannah; Beechem, Joseph M; Castillo, Carlos Fernandez-Del; Mino-Kenudson, Mari; Ting, David T; Hemberg, Martin; Hwang, William L.
Afiliación
  • Shiau C; Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Cao J; Department of Radiation Oncology, Massachusetts General Hospital, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Gong D; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Gregory MT; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Caldwell NJ; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Yin X; Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Cho JW; Department of Radiation Oncology, Massachusetts General Hospital, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Wang PL; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Su J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Wang S; Harvard-MIT Health Sciences and Technology Program, Cambridge, MA, USA.
  • Reeves JW; NanoString Technologies, Seattle, WA, USA.
  • Kim TK; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Kim Y; Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Guo JA; Department of Radiation Oncology, Massachusetts General Hospital, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Lester NA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Bae JW; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Zhao R; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Schurman N; Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Barth JL; Department of Radiation Oncology, Massachusetts General Hospital, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Ganci ML; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Weissleder R; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Jacks T; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Qadan M; Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Hong TS; Department of Radiation Oncology, Massachusetts General Hospital, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Wo JY; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Roberts H; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Beechem JM; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Castillo CF; Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Mino-Kenudson M; Department of Radiation Oncology, Massachusetts General Hospital, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Ting DT; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Hemberg M; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Hwang WL; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nat Genet ; 2024 Sep 03.
Article en En | MEDLINE | ID: mdl-39227743
ABSTRACT
In combination with cell-intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell-cell interactions in human pancreatic cancer associated with neoadjuvant chemotherapy and radiotherapy. We developed spatially constrained optimal transport interaction analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand-receptor gene expression. Our results uncovered a marked change in ligand-receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid coculture system. We identified enrichment in interleukin-6 family signaling that functionally confers resistance to chemotherapy. Overall, this study demonstrates that characterization of the tumor microenvironment using single-cell spatial transcriptomics allows for the identification of molecular interactions that may play a role in the emergence of therapeutic resistance and offers a spatially based analysis framework that can be broadly applied to other contexts.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos