Therapy-associated remodeling of pancreatic cancer revealed by single-cell spatial transcriptomics and optimal transport analysis.

Journal

bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187

Informations de publication

Date de publication:
29 Jun 2023
Historique:
pubmed: 10 7 2023
medline: 10 7 2023
entrez: 10 7 2023
Statut: epublish

Résumé

In combination with cell intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged high-plex single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell-cell interactions in human pancreatic cancer associated with specific malignant subtypes and neoadjuvant chemotherapy/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

Identifiants

DOI: 10.1101/2023.06.28.546848 PMID: 37425692 PMC: PMC10327107
pubmed: 37425692
doi: 10.1101/2023.06.28.546848
pmc: PMC10327107
pii:
doi:

Types de publication

Preprint

Langues

eng

Subventions

Organisme : NCI NIH HHS
ID : K08 CA270417
Pays : United States

Déclaration de conflit d'intérêts

W.L.H. and C.S. have received conference travel reimbursements from Nanostring Technologies related to presentation of some work in this study. M.H. is an SAB member and owns stocks in Neomer Diagnostics unrelated to this study. M.T.G., J.W.R., T.K.K., Y.K., N.S., and J.M.B. are employees of Nanostring Technologies. D.T.T. has received an honorarium from Nanostring Technologies, which had technology used in this manuscript. D.T.T. has received consulting fees from ROME Therapeutics and Tekla Capital not related to this work. D.T.T. has received honorariums from Moderna, Ikena Oncology, Foundation Medicine, Inc., and Pfizer that are not related to this work. D.T.T. is a founder and has equity in ROME Therapeutics, PanTher Therapeutics and TellBio, Inc., which is not related to this work. D.T.T. receives research support from ACD-Biotechne, PureTech Health LLC, Ribon Therapeutics, AVA LifeScience GmbH, and Incyte, which was not used in this work. W.L.H., J.A.G., and T.J. (U.S. Provisional Application No. 63/069,035) and W.L.H., J.A.G., C.S., J.S., and T.J. (U.S. Provisional Application No. 63/346,670) are co-inventors on provisional patents related to the pancreatic cancer states used in this study. The interests of M.H., W.L.H., and D.T.T. were reviewed and are managed by Mass General Brigham in accordance with their conflict of interest policies. T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific, and a co-Founder of Dragonfly Therapeutics and T2 Biosystems. T.J. serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics. T.J. is also President of Break Through Cancer. His laboratory currently receives funding from Johnson & Johnson, but these funds did not support the research described in this manuscript. All other authors declare no interests related to this work.

Auteurs

Carina Shiau (C)

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Jingyi Cao (J)

Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Mark T Gregory (MT)

NanoString Technologies, Seattle, WA, USA.

Dennis Gong (D)

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard-MIT Health Sciences and Technology Program, Cambridge, MA, USA.

Xunqin Yin (X)

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Jae-Won Cho (JW)

Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Peter L Wang (PL)

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.

Jennifer Su (J)

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.

Steven Wang (S)

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.

Jason W Reeves (JW)

NanoString Technologies, Seattle, WA, USA.

Tae Kyung Kim (TK)

NanoString Technologies, Seattle, WA, USA.

Youngmi Kim (Y)

NanoString Technologies, Seattle, WA, USA.

Jimmy A Guo (JA)

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA, USA.

Nicole A Lester (NA)

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.

Nathan Schurman (N)

NanoString Technologies, Seattle, WA, USA.

Jamie L Barth (JL)

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Ralph Weissleder (R)

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Tyler Jacks (T)

Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.

Motaz Qadan (M)

Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Theodore S Hong (TS)

Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Jennifer Y Wo (JY)

Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Hannah Roberts (H)

Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Joseph M Beechem (JM)

NanoString Technologies, Seattle, WA, USA.

Carlos Fernandez-Del Castillo (CF)

Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Mari Mino-Kenudson (M)

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

David T Ting (DT)

Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Martin Hemberg (M)

Broad Institute of MIT and Harvard, Cambridge, MA, USA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

William L Hwang (WL)

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.

Classifications MeSH