LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy

Oncogene
Leonie RossowErik Henke

Abstract

The potential of altering the tumor ECM to improve drug response remains fairly unexplored. To identify targets for modification of the ECM aiming to improve drug response and overcome resistance, we analyzed expression data sets from pre-treatment patient cohorts. Cross-evaluation identified a subset of chemoresistant tumors characterized by increased expression of collagens and collagen-stabilizing enzymes. We demonstrate that strong collagen expression and stabilization sets off a vicious circle of self-propagating hypoxia, malignant signaling, and aberrant angiogenesis that can be broken by an appropriate auxiliary intervention: Interfering with collagen stabilization by inhibition of lysyl oxidases significantly enhanced response to chemotherapy in various tumor models, even in metastatic disease. Inhibition of collagen stabilization by itself can reduce or enhance tumor growth depending on the tumor type. The mechanistical basis for this behavior is the dependence of the individual tumor on nutritional supply on one hand and on high tissue stiffness for FAK signaling on the other.

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Citations

Oct 27, 2018·Histochemistry and Cell Biology·Rajender NandigamaErik Henke
Nov 27, 2019·Cells·Cristina Rodríguez, José Martínez-González
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Datasets Mentioned

BETA
GDS3721
GSE25066
GSE4393

Methods Mentioned

BETA
biopsies
transfect
Assay

Key Resources (RRID) Mentioned

AB_2341188
AB_2066539
AB_1108863
AB_2267979
AB_306316
AB_2082660
AB_302459
AB_1930256
AB_10987961
AB_630835

Software Mentioned

ClustalX
GeXP
Treeview
power
BRB
Array
ImageJ
Prism5
ArrayTools

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