% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Daum:302109,
      author       = {A.-K. Daum$^*$ and L. Schlicker$^*$ and M. A. Schneider and
                      T. Muley and U. Klingmüller$^*$ and A. Schulze$^*$ and M.
                      Thomas and P. Christopoulos and H. Sültmann$^*$},
      title        = {{C}ancer-associated fibroblasts promote drug resistance in
                      {ALK}-driven lung adenocarcinoma cells by upregulating lipid
                      biosynthesis.},
      journal      = {Cancer $\&$ metabolism},
      volume       = {13},
      number       = {1},
      issn         = {2049-3002},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DKFZ-2025-01241},
      pages        = {28},
      year         = {2025},
      note         = {#EA:B063#LA:B063#},
      abstract     = {Targeted therapy interventions using tyrosine kinase
                      inhibitors (TKIs) provide encouraging treatment responses in
                      patients with ALK-rearranged lung adenocarcinomas, yet
                      resistance occurs almost inevitably. In addition to tumor
                      cell-intrinsic resistance mechanisms, accumulating evidence
                      suggests that cancer-associated fibroblasts (CAFs) within
                      the tumor microenvironment contribute to therapy resistance.
                      This study aimed to investigate CAF-driven molecular
                      networks that shape the therapeutic susceptibility of
                      ALK-driven lung adenocarcinoma cells.Three-dimensional (3D)
                      spheroid co-cultures comprising ALK-rearranged lung
                      adenocarcinoma cells and CAFs were utilized to model the
                      tumor microenvironment. Single-cell RNA sequencing was
                      performed to uncover transcriptional differences between
                      TKI-treated homotypic and heterotypic spheroids. Functional
                      assays assessed the effects of CAF-conditioned medium and
                      CAF-secreted factors on tumor cell survival, proliferation,
                      lipid metabolism, and downstream AKT signaling. The
                      therapeutic potential of targeting metabolic vulnerabilities
                      was evaluated using pharmacological inhibition of lipid
                      metabolism and by ferroptosis induction.CAFs significantly
                      diminished the apoptotic response of lung tumor cells to ALK
                      inhibitors while simultaneously enhancing their
                      proliferative capacity. Single-cell RNA sequencing
                      identified lipogenesis-associated genes as a key
                      transcriptional difference between TKI-treated homotypic and
                      heterotypic lung tumor spheroids. CAF-conditioned medium and
                      the CAF-secreted factors HGF and NRG1 activated AKT
                      signaling in 3D-cultured ALK-rearranged lung tumor cells,
                      leading to increased de novo lipogenesis and suppression of
                      lipid peroxidation. These metabolic adaptations were
                      critical for promoting tumor cell survival and fostering
                      therapy resistance. Notably, both dual inhibition of ALK and
                      the lipid-regulatory factor SREBP-1, as well as co-treatment
                      with ferroptosis inducers such as erastin or RSL3,
                      effectively disrupted the CAF-driven metabolic-supportive
                      niche and restored sensitivity of resistant lung tumor
                      spheroids to ALK inhibition.This study highlights a critical
                      role for CAFs in mediating resistance to ALK-TKIs by
                      reprogramming lipid metabolism in ALK-rearranged lung cancer
                      cells. It suggests that targeting these metabolic
                      vulnerabilities, particularly through inhibition of lipid
                      metabolism or induction of ferroptosis, could provide a
                      novel therapeutic approach to overcome resistance and
                      improve patient outcomes.},
      keywords     = {3D cell culture (Other) / Cancer-associated fibroblasts
                      (Other) / EML4-ALK (Other) / Lipid metabolism (Other) / Lung
                      adenocarcinoma (Other) / Therapy resistance (Other)},
      cin          = {B063 / HD01 / A410 / W120 / B200},
      ddc          = {610},
      cid          = {I:(DE-He78)B063-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)A410-20160331 / I:(DE-He78)W120-20160331 /
                      I:(DE-He78)B200-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40524253},
      pmc          = {pmc:PMC12168422},
      doi          = {10.1186/s40170-025-00400-7},
      url          = {https://inrepo02.dkfz.de/record/302109},
}