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 Citations (Scopus)

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

Fingerprint

Plasminogen Activator Inhibitor 2
Autophagy
Plasminogen Activator Inhibitor 1
Caveolin 1
Fibroblasts
Neoplasm Metastasis
Neoplasms
Heterografts
Extracellular Matrix
Breast
Breast Neoplasms
Organelle Biogenesis
Coculture Techniques
Proteomics
Down-Regulation
Eating
Epithelial Cells
Apoptosis
Phenotype
Cell Line

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

Castello-Cros, R., Bonuccelli, G., Molchansky, A., Capozza, F., Witkiewicz, A. K., Birbe, R. C., ... 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

Matrix remodeling stimulates stromal autophagy, "fueling" cancer cell mitochondrial metabolism and metastasis. / Castello-Cros, Remedios; Bonuccelli, Gloria; Molchansky, Alex; Capozza, Franco; Witkiewicz, Agnieszka K.; Birbe, Ruth C.; Howell, Anthony; Pestell, Richard G.; Whitaker-Menezes, Diana; Sotgia, Federica; Lisanti, Michael P.

In: Cell Cycle, Vol. 10, No. 12, 15.06.2011, p. 2021-2034.

Research output: Contribution to journalArticle

Castello-Cros, R, Bonuccelli, G, Molchansky, A, Capozza, F, Witkiewicz, AK, Birbe, RC, Howell, A, Pestell, RG, Whitaker-Menezes, D, Sotgia, F & Lisanti, MP 2011, 'Matrix remodeling stimulates stromal autophagy, "fueling" cancer cell mitochondrial metabolism and metastasis', Cell Cycle, vol. 10, no. 12, pp. 2021-2034. https://doi.org/10.4161/cc.10.12.16002
Castello-Cros, Remedios ; Bonuccelli, Gloria ; Molchansky, Alex ; Capozza, Franco ; Witkiewicz, Agnieszka K. ; Birbe, Ruth C. ; Howell, Anthony ; Pestell, Richard G. ; Whitaker-Menezes, Diana ; Sotgia, Federica ; Lisanti, Michael P. / Matrix remodeling stimulates stromal autophagy, "fueling" cancer cell mitochondrial metabolism and metastasis. In: Cell Cycle. 2011 ; Vol. 10, No. 12. pp. 2021-2034.
@article{c6d071220c3f40b3a2a1462dccb56fc9,
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 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.",
keywords = "Apoptosis, Autophagy, Breast cancer, Cancer-associated fibroblasts, Caveolin-1, Metastasis, Plasminogen activator inhibitor, Tumor stroma",
author = "Remedios Castello-Cros and Gloria Bonuccelli and Alex Molchansky and Franco Capozza and Witkiewicz, {Agnieszka K.} and Birbe, {Ruth C.} and Anthony Howell and Pestell, {Richard G.} and Diana Whitaker-Menezes and Federica Sotgia and Lisanti, {Michael P.}",
year = "2011",
month = "6",
day = "15",
doi = "10.4161/cc.10.12.16002",
language = "English (US)",
volume = "10",
pages = "2021--2034",
journal = "Cell Cycle",
issn = "1538-4101",
publisher = "Landes Bioscience",
number = "12",

}

TY - JOUR

T1 - Matrix remodeling stimulates stromal autophagy, "fueling" cancer cell mitochondrial metabolism and metastasis

AU - Castello-Cros, Remedios

AU - Bonuccelli, Gloria

AU - Molchansky, Alex

AU - Capozza, Franco

AU - Witkiewicz, Agnieszka K.

AU - Birbe, Ruth C.

AU - Howell, Anthony

AU - Pestell, Richard G.

AU - Whitaker-Menezes, Diana

AU - Sotgia, Federica

AU - Lisanti, Michael P.

PY - 2011/6/15

Y1 - 2011/6/15

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Autophagy

KW - Breast cancer

KW - Cancer-associated fibroblasts

KW - Caveolin-1

KW - Metastasis

KW - Plasminogen activator inhibitor

KW - Tumor stroma

UR - http://www.scopus.com/inward/record.url?scp=79959282414&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79959282414&partnerID=8YFLogxK

U2 - 10.4161/cc.10.12.16002

DO - 10.4161/cc.10.12.16002

M3 - Article

VL - 10

SP - 2021

EP - 2034

JO - Cell Cycle

JF - Cell Cycle

SN - 1538-4101

IS - 12

ER -