Collagen production and niche engineering: A novel strategy for cancer cells to survive acidosis in DCIS and evolve.

Mehdi Damaghi,Samantha Byrne,Joseph Johnson,Hidetoshi Mori,Liping Xu,Robert J Gillies,Alexander D Borowsky,Andriy Marusyk,Nathan D Gallant,Tingan Chen

doi:10.1111/eva.13075

Abstract

Growing tumors are dynamic and nonlinear ecosystems, wherein cancer cells adapt to their local microenvironment, and these adaptations further modify the environment, inducing more changes. From nascent intraductal neoplasms to disseminated metastatic disease, several levels of evolutionary adaptations and selections occur. Here, we focus on one example of such an adaptation mechanism, namely, “niche construction” promoted by adaptation to acidosis, which is a metabolic adaptation to the early harsh environment in intraductal neoplasms. The avascular characteristics of ductal carcinoma in situ (DCIS) make the periluminal volume profoundly acidic, and cancer cells must adapt to this to survive. Based on discovery proteomics, we hypothesized that a component of acid adaptation involves production of collagen by pre‐cancer cells that remodels the extracellular matrix (ECM) and stabilizes cells under acid stress. The proteomic data were surprising as collagen production and deposition are commonly believed to be the responsibility of mesenchymally derived fibroblasts, and not cells of epithelial origin. Subsequent experiments in 3D culture, spinning disk and second harmonic generation microscopy of DCIS lesions in patients’ samples are concordant. Collagen production assay by acid‐adapted cells in vitro demonstrated that the mechanism of induction involves the RAS and SMAD pathways. Secretome analyses show upregulation of ECM remodeling enzymes such as TGM2 and LOXL2 that are collagen crosslinkers. These data strongly indicate that acidosis in incipient cancers induces collagen production by cancer cells and support the hypothesis that this adaptation initiates a tumor‐permissive microenvironment promoting survival and growth of nascent cancers.

Highlights

The earliest stages of carcinogenesis are not known with certainty
The attachment of epithelial cells to the basement membrane substratum is necessary for their survival, which is promoted by collagen activation of focal adhesion kinases, FAKs [8, 9]
We have proposed that cell death imposed by loss of basement membrane attachment (“anoikis”) is one of the first evolutionary barriers that cancer cells reach in their early progression [19] and we investigated whether acidosis would effect this process

Summary

Introduction

Breast cancers are initiated by intraductal hyperplasia which is likely triggered by chronic inflammation [1,2,3,4,5] This involves cells growing into the ductal lumen, which requires them to detach from their normal niche which is attached to a basement membrane (BM) [6, 7]. Since the blood supply for these cells resides in the surrounding stroma, as hyperplasic cells grow to the lumen, they become increasingly hypoxic [12] This hypoxia, along with nutrient deprivation, selects for cells with the phenotype of aerobic glycolysis, known as the Warburg Effect, WE [11, 13]. Cancer cells must eventually adapt to this harsh acidic environment [4] that arises phenotypic resistance to acid-induced apoptosis [4, 22]

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Results

Discussion

Conclusion