2. Academic Validation
  3. Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms

Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms

  • Cancer Cell. 2021 Nov 8;39(11):1531-1547.e10. doi: 10.1016/j.ccell.2021.09.003.
Haichuan Hu 1,  Zofia Piotrowska 2,  Patricia J Hare 2,  Huidong Chen 3,  Hillary E Mulvey 2,  Aislinn Mayfield 2,  Sundus Noeen 2,  Krystina Kattermann 2,  Max Greenberg 2,  August Williams 2,  Amanda K Riley 2,  Jarad J Wilson 4,  Ying-Qing Mao 5,  Ruo-Pan Huang 6,  Mandeep K Banwait 2,  Jeffrey Ho 2,  Giovanna S Crowther 2,  Lida P Hariri 7,  Rebecca S Heist 2,  David P Kodack 8,  Luca Pinello 3,  Alice T Shaw 2,  Mari Mino-Kenudson 7,  Aaron N Hata 2,  Lecia V Sequist 2,  Cyril H Benes 9,  Matthew J Niederst 10,  Jeffrey A Engelman 11
Affiliations

Affiliations

  • 1 Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA. Electronic address: hhu5@mgh.harvard.edu.
  • 2 Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
  • 3 Massachusetts General Hospital and Department of Pathology, Harvard Medical School, Boston, MA 02114, USA; Molecular Pathology Unit, Massachusetts General Hospital Research Institute, Charlestown, MA 02129, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • 4 RayBiotech Inc, Norcross, GA 30092, USA.
  • 5 RayBiotech Inc, Norcross, GA 30092, USA; RayBiotech Inc, Guangzhou, Guangdong 510630, China.
  • 6 RayBiotech Inc, Norcross, GA 30092, USA; RayBiotech Inc, Guangzhou, Guangdong 510630, China; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong 510095, China.
  • 7 Massachusetts General Hospital and Department of Pathology, Harvard Medical School, Boston, MA 02114, USA.
  • 8 Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
  • 9 Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA. Electronic address: cyrilbenes@gmail.com.
  • 10 Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. Electronic address: matt.niederst@novartis.com.
  • 11 Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. Electronic address: jengelman1@gmail.com.
PMID: 34624218 DOI: 10.1016/j.ccell.2021.09.003
Abstract

Cancer-associated fibroblasts (CAFs) are highly heterogeneous. With the lack of a comprehensive understanding of CAFs' functional distinctions, it remains unclear how Cancer treatments could be personalized based on CAFs in a patient's tumor. We have established a living biobank of CAFs derived from biopsies of patients' non-small lung Cancer (NSCLC) that encompasses a broad molecular spectrum of CAFs in clinical NSCLC. By functionally interrogating CAF heterogeneity using the same therapeutics received by patients, we identify three functional subtypes: (1) robustly protective of cancers and highly expressing HGF and FGF7; (2) moderately protective of cancers and highly expressing FGF7; and (3) those providing minimal protection. These functional differences among CAFs are governed by their intrinsic TGF-β signaling, which suppresses HGF and FGF7 expression. This CAF functional classification correlates with patients' clinical response to targeted therapies and also associates with the tumor immune microenvironment, therefore providing an avenue to guide personalized treatment.

Keywords

cancer therapy; cancer-associated fibroblasts; lung cancer; patient-derived models; personalized medicine; resistance; targeted therapy; tumor heterogeneity; tumor microenvironment; tumor-infiltrating lymphocytes.

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