title: Matrix remodeling stimulates stromal autophagy, "fueling" cancer cell mitochondrial metabolism and metastasis.
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 microenvironment 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 revealed 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.
authors.affiliation: The Jefferson Stem Cell Biology and Regenerative Medicine Center, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. remedios.castello@jefferson.edu
authors.forename: Remedios
authors.initials: R
authors.lastname: Castello-Cros
authors.forename: Gloria
authors.initials: G
authors.lastname: Bonuccelli
authors.forename: Alex
authors.initials: A
authors.lastname: Molchansky
authors.forename: Franco
authors.initials: F
authors.lastname: Capozza
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Birbe
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Diana
authors.initials: D
authors.lastname: Whitaker-Menezes
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000818:Animals; D001343:Autophagy; D001943:Breast Neoplasms / Q000473:pathology; D051242:Caveolin 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology / Q000648:ultrastructure; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism; D017154:Stromal Cells / Q000473:pathology*; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment
chemical_list: D051242:Caveolin 1; D017395:Plasminogen Activator Inhibitor 1; D017396:Plasminogen Activator Inhibitor 2