AXL-associated tumor inflammation as a poor prognostic signature in chemotherapy-treated triple-negative breast cancer patients

Giulia Bottai, Carlotta Raschioni, Borbála Székely, Luca Di Tommaso, A. Szász, Agnese Losurdo, B. Györffy, Balázs Ács, Rosalba Torrisi, Niki Karachaliou, Tímea Tőkés, Michele Caruso, J. Kulka, Massimo Roncalli, Armando Santoro, Alberto Mantovani, Rafael Rosell, Jorge S. Reis-Filho, Libero Santarpia

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

A subgroup of triple-negative breast cancer (TNBC) shows epithelial-to-mesenchymal transition (EMT) features, which are sustained by the interaction between cancer cells and tumor-associated macrophages (TAMs). In this study, the clinical relevance of 30 EMT-related kinases and the potential cross-talk with TAMs were investigated in a cohort of 203 TNBC patients treated with adjuvant chemotherapy. The prognostic value of the evaluated markers was validated in two independent cohorts of TNBC patients treated with adjuvant chemotherapy (N = 95; N = 137). In vitro, we investigated the potential synergism between cancer cells and TAMs. We found that the EMT-related kinase AXL showed the highest correlation with the frequency of CD163-positive macrophages (r S = 0.503; P<0.0001). Relapsing TNBC patients presented high expression of AXL (P<0.0001) and CD163 (P<0.018), but only AXL retained independent prognostic significance in multivariate analysis (relapse-free survival, P = 0.002; overall survival P = 0.001). In vitro analysis demonstrated that AXL-expressing TNBC cells were able to polarize human macrophages towards an M2-like phenotype, and modulate a specific pattern of pro-tumor cytokines and chemokines. Selective AXL inhibition impaired the activity of M2-like macrophages, reducing cancer cell invasiveness, and restoring the sensitivity of breast cancer cells to chemotherapeutic drugs. These data suggest that the EMT-related kinase AXL overexpressed in cancer cells has prognostic significance, and contributes to the functional skewing of macrophage functions in TNBC. AXL inhibition may represent a novel strategy to target cancer cells, as well as tumor-promoting TAMs in TNBC.

Original languageEnglish
Article number16033
Journalnpj Breast Cancer
Volume2
Issue number1
DOIs
Publication statusPublished - Dec 14 2016

Fingerprint

Triple Negative Breast Neoplasms
Inflammation
Drug Therapy
Macrophages
Epithelial-Mesenchymal Transition
Neoplasms
Phosphotransferases
Adjuvant Chemotherapy
Survival
Chemokines
Multivariate Analysis

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Pharmacology (medical)

Cite this

AXL-associated tumor inflammation as a poor prognostic signature in chemotherapy-treated triple-negative breast cancer patients. / Bottai, Giulia; Raschioni, Carlotta; Székely, Borbála; Di Tommaso, Luca; Szász, A.; Losurdo, Agnese; Györffy, B.; Ács, Balázs; Torrisi, Rosalba; Karachaliou, Niki; Tőkés, Tímea; Caruso, Michele; Kulka, J.; Roncalli, Massimo; Santoro, Armando; Mantovani, Alberto; Rosell, Rafael; Reis-Filho, Jorge S.; Santarpia, Libero.

In: npj Breast Cancer, Vol. 2, No. 1, 16033, 14.12.2016.

Research output: Contribution to journalArticle

Bottai, G, Raschioni, C, Székely, B, Di Tommaso, L, Szász, A, Losurdo, A, Györffy, B, Ács, B, Torrisi, R, Karachaliou, N, Tőkés, T, Caruso, M, Kulka, J, Roncalli, M, Santoro, A, Mantovani, A, Rosell, R, Reis-Filho, JS & Santarpia, L 2016, 'AXL-associated tumor inflammation as a poor prognostic signature in chemotherapy-treated triple-negative breast cancer patients', npj Breast Cancer, vol. 2, no. 1, 16033. https://doi.org/10.1038/npjbcancer.2016.33
Bottai, Giulia ; Raschioni, Carlotta ; Székely, Borbála ; Di Tommaso, Luca ; Szász, A. ; Losurdo, Agnese ; Györffy, B. ; Ács, Balázs ; Torrisi, Rosalba ; Karachaliou, Niki ; Tőkés, Tímea ; Caruso, Michele ; Kulka, J. ; Roncalli, Massimo ; Santoro, Armando ; Mantovani, Alberto ; Rosell, Rafael ; Reis-Filho, Jorge S. ; Santarpia, Libero. / AXL-associated tumor inflammation as a poor prognostic signature in chemotherapy-treated triple-negative breast cancer patients. In: npj Breast Cancer. 2016 ; Vol. 2, No. 1.
@article{b91bb13574b244739d9647272c84d744,
title = "AXL-associated tumor inflammation as a poor prognostic signature in chemotherapy-treated triple-negative breast cancer patients",
abstract = "A subgroup of triple-negative breast cancer (TNBC) shows epithelial-to-mesenchymal transition (EMT) features, which are sustained by the interaction between cancer cells and tumor-associated macrophages (TAMs). In this study, the clinical relevance of 30 EMT-related kinases and the potential cross-talk with TAMs were investigated in a cohort of 203 TNBC patients treated with adjuvant chemotherapy. The prognostic value of the evaluated markers was validated in two independent cohorts of TNBC patients treated with adjuvant chemotherapy (N = 95; N = 137). In vitro, we investigated the potential synergism between cancer cells and TAMs. We found that the EMT-related kinase AXL showed the highest correlation with the frequency of CD163-positive macrophages (r S = 0.503; P<0.0001). Relapsing TNBC patients presented high expression of AXL (P<0.0001) and CD163 (P<0.018), but only AXL retained independent prognostic significance in multivariate analysis (relapse-free survival, P = 0.002; overall survival P = 0.001). In vitro analysis demonstrated that AXL-expressing TNBC cells were able to polarize human macrophages towards an M2-like phenotype, and modulate a specific pattern of pro-tumor cytokines and chemokines. Selective AXL inhibition impaired the activity of M2-like macrophages, reducing cancer cell invasiveness, and restoring the sensitivity of breast cancer cells to chemotherapeutic drugs. These data suggest that the EMT-related kinase AXL overexpressed in cancer cells has prognostic significance, and contributes to the functional skewing of macrophage functions in TNBC. AXL inhibition may represent a novel strategy to target cancer cells, as well as tumor-promoting TAMs in TNBC.",
author = "Giulia Bottai and Carlotta Raschioni and Borb{\'a}la Sz{\'e}kely and {Di Tommaso}, Luca and A. Sz{\'a}sz and Agnese Losurdo and B. Gy{\"o}rffy and Bal{\'a}zs {\'A}cs and Rosalba Torrisi and Niki Karachaliou and T{\'i}mea Tők{\'e}s and Michele Caruso and J. Kulka and Massimo Roncalli and Armando Santoro and Alberto Mantovani and Rafael Rosell and Reis-Filho, {Jorge S.} and Libero Santarpia",
year = "2016",
month = "12",
day = "14",
doi = "10.1038/npjbcancer.2016.33",
language = "English",
volume = "2",
journal = "npj Breast Cancer",
issn = "2374-4677",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - AXL-associated tumor inflammation as a poor prognostic signature in chemotherapy-treated triple-negative breast cancer patients

AU - Bottai, Giulia

AU - Raschioni, Carlotta

AU - Székely, Borbála

AU - Di Tommaso, Luca

AU - Szász, A.

AU - Losurdo, Agnese

AU - Györffy, B.

AU - Ács, Balázs

AU - Torrisi, Rosalba

AU - Karachaliou, Niki

AU - Tőkés, Tímea

AU - Caruso, Michele

AU - Kulka, J.

AU - Roncalli, Massimo

AU - Santoro, Armando

AU - Mantovani, Alberto

AU - Rosell, Rafael

AU - Reis-Filho, Jorge S.

AU - Santarpia, Libero

PY - 2016/12/14

Y1 - 2016/12/14

N2 - A subgroup of triple-negative breast cancer (TNBC) shows epithelial-to-mesenchymal transition (EMT) features, which are sustained by the interaction between cancer cells and tumor-associated macrophages (TAMs). In this study, the clinical relevance of 30 EMT-related kinases and the potential cross-talk with TAMs were investigated in a cohort of 203 TNBC patients treated with adjuvant chemotherapy. The prognostic value of the evaluated markers was validated in two independent cohorts of TNBC patients treated with adjuvant chemotherapy (N = 95; N = 137). In vitro, we investigated the potential synergism between cancer cells and TAMs. We found that the EMT-related kinase AXL showed the highest correlation with the frequency of CD163-positive macrophages (r S = 0.503; P<0.0001). Relapsing TNBC patients presented high expression of AXL (P<0.0001) and CD163 (P<0.018), but only AXL retained independent prognostic significance in multivariate analysis (relapse-free survival, P = 0.002; overall survival P = 0.001). In vitro analysis demonstrated that AXL-expressing TNBC cells were able to polarize human macrophages towards an M2-like phenotype, and modulate a specific pattern of pro-tumor cytokines and chemokines. Selective AXL inhibition impaired the activity of M2-like macrophages, reducing cancer cell invasiveness, and restoring the sensitivity of breast cancer cells to chemotherapeutic drugs. These data suggest that the EMT-related kinase AXL overexpressed in cancer cells has prognostic significance, and contributes to the functional skewing of macrophage functions in TNBC. AXL inhibition may represent a novel strategy to target cancer cells, as well as tumor-promoting TAMs in TNBC.

AB - A subgroup of triple-negative breast cancer (TNBC) shows epithelial-to-mesenchymal transition (EMT) features, which are sustained by the interaction between cancer cells and tumor-associated macrophages (TAMs). In this study, the clinical relevance of 30 EMT-related kinases and the potential cross-talk with TAMs were investigated in a cohort of 203 TNBC patients treated with adjuvant chemotherapy. The prognostic value of the evaluated markers was validated in two independent cohorts of TNBC patients treated with adjuvant chemotherapy (N = 95; N = 137). In vitro, we investigated the potential synergism between cancer cells and TAMs. We found that the EMT-related kinase AXL showed the highest correlation with the frequency of CD163-positive macrophages (r S = 0.503; P<0.0001). Relapsing TNBC patients presented high expression of AXL (P<0.0001) and CD163 (P<0.018), but only AXL retained independent prognostic significance in multivariate analysis (relapse-free survival, P = 0.002; overall survival P = 0.001). In vitro analysis demonstrated that AXL-expressing TNBC cells were able to polarize human macrophages towards an M2-like phenotype, and modulate a specific pattern of pro-tumor cytokines and chemokines. Selective AXL inhibition impaired the activity of M2-like macrophages, reducing cancer cell invasiveness, and restoring the sensitivity of breast cancer cells to chemotherapeutic drugs. These data suggest that the EMT-related kinase AXL overexpressed in cancer cells has prognostic significance, and contributes to the functional skewing of macrophage functions in TNBC. AXL inhibition may represent a novel strategy to target cancer cells, as well as tumor-promoting TAMs in TNBC.

UR - http://www.scopus.com/inward/record.url?scp=85047147370&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047147370&partnerID=8YFLogxK

U2 - 10.1038/npjbcancer.2016.33

DO - 10.1038/npjbcancer.2016.33

M3 - Article

AN - SCOPUS:85047147370

VL - 2

JO - npj Breast Cancer

JF - npj Breast Cancer

SN - 2374-4677

IS - 1

M1 - 16033

ER -