Spatially confined sub-tumor microenvironments in pancreatic cancer

Barbara T Grünwald¹, Antoine Devisme², Geoffroy Andrieux³, Foram Vyas⁴, Kazeera Aliar¹, Curtis W McCloskey¹, Andrew Macklin¹, Gun Ho Jang⁵, Robert Denroche⁵, Joan Miguel Romero⁵, Prashant Bavi⁶, Peter Bronsert⁷, Faiyaz Notta⁸, Grainne O'Kane⁹, Julie Wilson⁵, Jennifer Knox⁹, Laura Tamblyn¹⁰, Molly Udaskin¹⁰, Nikolina Radulovich¹⁰, Sandra E Fischer¹¹, Melanie Boerries¹², Steven Gallinger¹³, Thomas Kislinger¹⁴, Rama Khokha¹⁵

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
² Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79110 Freiburg, Germany.
³ Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, 79110 Freiburg, Germany.
⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
⁵ PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
⁶ PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON M5G 2M9, Canada.
⁷ Core Facility for Histopathology and Digital Pathology, Medical Center-University of Freiburg, 79106 Freiburg, Germany.
⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
⁹ PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
¹⁰ Princess Margaret Living Biobank Core, University Health Network, Toronto, ON M5G 1L7, Canada.
¹¹ Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON M5G 2M9, Canada; Division of Anatomic Pathology, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada.
¹² Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, 79110 Freiburg, Germany. Electronic address: m.boerries@dkfz-heidelberg.de.
¹³ PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada; Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON M5G 2M9, Canada. Electronic address: steven.gallinger@uhn.ca.
¹⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. Electronic address: thomas.kislinger@utoronto.ca.
¹⁵ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. Electronic address: rama.khokha@uhnresearch.ca.

PMID: 34644529
DOI: 10.1016/j.cell.2021.09.022

Free article

Spatially confined sub-tumor microenvironments in pancreatic cancer

Barbara T Grünwald et al. Cell. 2021.

Free article

. 2021 Oct 28;184(22):5577-5592.e18.

doi: 10.1016/j.cell.2021.09.022. Epub 2021 Oct 12.

Authors

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
² Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79110 Freiburg, Germany.
³ Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, 79110 Freiburg, Germany.
⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
⁵ PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
⁶ PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON M5G 2M9, Canada.
⁷ Core Facility for Histopathology and Digital Pathology, Medical Center-University of Freiburg, 79106 Freiburg, Germany.
⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
⁹ PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
¹⁰ Princess Margaret Living Biobank Core, University Health Network, Toronto, ON M5G 1L7, Canada.
¹¹ Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON M5G 2M9, Canada; Division of Anatomic Pathology, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada.
¹² Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, 79110 Freiburg, Germany. Electronic address: m.boerries@dkfz-heidelberg.de.
¹³ PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada; Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON M5G 2M9, Canada. Electronic address: steven.gallinger@uhn.ca.
¹⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. Electronic address: thomas.kislinger@utoronto.ca.
¹⁵ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. Electronic address: rama.khokha@uhnresearch.ca.

PMID: 34644529
DOI: 10.1016/j.cell.2021.09.022

Abstract

Intratumoral heterogeneity is a critical frontier in understanding how the tumor microenvironment (TME) propels malignant progression. Here, we deconvolute the human pancreatic TME through large-scale integration of histology-guided regional multiOMICs with clinical data and patient-derived preclinical models. We discover "subTMEs," histologically definable tissue states anchored in fibroblast plasticity, with regional relationships to tumor immunity, subtypes, differentiation, and treatment response. "Reactive" subTMEs rich in complex but functionally coordinated fibroblast communities were immune hot and inhabited by aggressive tumor cell phenotypes. The matrix-rich "deserted" subTMEs harbored fewer activated fibroblasts and tumor-suppressive features yet were markedly chemoprotective and enriched upon chemotherapy. SubTMEs originated in fibroblast differentiation trajectories, and transitory states were notable both in single-cell transcriptomics and in situ. The intratumoral co-occurrence of subTMEs produced patient-specific phenotypic and computationally predictable heterogeneity tightly linked to malignant biology. Therefore, heterogeneity within the plentiful, notorious pancreatic TME is not random but marks fundamental tissue organizational units.

Keywords: cancer-associated fibroblasts; pancreatic cancer; patient-derived organoids; proteomics; stromal heterogeneity; systems biology; treatment resistance; tumor microenvironment.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Spatially confined sub-tumor microenvironments in pancreatic cancer

Affiliations

Spatially confined sub-tumor microenvironments in pancreatic cancer

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases