Matrix remodeling stimulates stromal autophagy, "fueling" cancer cell mitochondrial metabolism and metastasis

Remedios Castello-Cros, Gloria Bonuccelli, Alex Molchansky, Franco Capozza, Agnieszka K. Witkiewicz, Ruth C. Birbe, Anthony Howell, Richard G. Pestell, Diana Whitaker-Menezes, Federica Sotgia, Michael P. Lisanti

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

We have previously demonstrated that loss of stromal caveolin-1 (Cav-1) in cancer-associated fibroblasts is a strong and independent predictor of poor clinical outcome in human breast cancer patients. However, the signaling mechanism(s) by which Cav-1 downregulation leads to this tumor-promoting micro-environment are not well understood. to address this issue, we performed an unbiased comparative proteomic analysis of wild-type (WT) and Cav-1 (-/-) null mammary stromal fibroblasts (MSFs). Our results show that plasminogen activator inhibitor type 1 and type 2 (PAI-1 and PAI-2) expression is significantly increased in Cav-1 (-/-) MSFs. To establish a direct cause-effect relationship, we next generated immortalized human fibroblast lines stably overexpressing either PAI-1 or PAI-2. Importantly, PAI-1/2(+) fibroblasts promote the growth of MDA-MB-231 tumors (a human breast cancer cell line) in a murine xenograft model, without any increases in angiogenesis. Similarly, PAI-1/2(+) fibroblasts stimulate experimental metastasis of MDA-MB-231 cells, using an in vivo lung colonization assay. Further mechanistic studies reveal that fibroblasts overexpressing PAI-1 or PAI-2 display increased autophagy ("self-eating"), and are sufficient to induce mitochondrial biogenesis/activity in adjacent cancer cells, in co-culture experiments. In xenografts, PAI-1/2(+) fibroblasts significantly reduce the apoptosis of MDA-MB-231 tumor cells. The current study provides further support for the "Autophagic Tumor Stroma Model of Cancer" and identifies a novel "extracellular-matrix"-based signaling mechanism by which a loss of stromal Cav-1 generates a metastatic phenotype. Thus, the secretion and remodeling of extracellular matrix components (such as PAI-1/2) can directly regulate both (1) autophagy in stromal fibroblasts and (2) epithelial tumor cell mitochondrial metabolism.

Original languageEnglish (US)
Pages (from-to)2021-2034
Number of pages14
JournalCell Cycle
Volume10
Issue number12
DOIs
StatePublished - Jun 15 2011

Keywords

  • Apoptosis
  • Autophagy
  • Breast cancer
  • Cancer-associated fibroblasts
  • Caveolin-1
  • Metastasis
  • Plasminogen activator inhibitor
  • Tumor stroma

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Castello-Cros, R., Bonuccelli, G., Molchansky, A., Capozza, F., Witkiewicz, A. K., Birbe, R. C., Howell, A., Pestell, R. G., Whitaker-Menezes, D., Sotgia, F., & Lisanti, M. P. (2011). Matrix remodeling stimulates stromal autophagy, "fueling" cancer cell mitochondrial metabolism and metastasis. Cell Cycle, 10(12), 2021-2034. https://doi.org/10.4161/cc.10.12.16002