Collagen Production and Niche Engineering: A Novel Strategy for Cancer Cells to Survive Acidosis and Evolve

Abstract

Ductal Carcinoma in situ (DCIS) is an avascular disease characterized by profound acidosis. Premalignant cells within this niche must adapt to acidosis to survive and thrive. A component of this acidadaptation involves extracellular matrix remodeling leading to niche construction and remodeling.Using discovery proteomics, we identified that collagen producing enzyme PLODs are upregulated in acid-adapted breast cancer cells. Second harmonic generation microscopy showed significant collagen deposition within DCIS lesions of patients. In vitro analyses identified that acid-adaptation involves production of rare collagens that can be regulated by Ras and SMAD pathway. Secretome analysis showed upregulation ECM remodeling enzymes such as TGM2 and LOXL2. Comparison of acid induced collagens in vitro and in patient data showed correlation between rare collagens production and survival of patients. We conclude acidosis induces collagen production by cancer cells and promote growth independent of basal membrane attachment. The independently produced collagen can be used for niche construction and engineering as an adaptation strategy of cancer cells to survive and evolve.

Mix and Match: Phenotypic Coexistence as a Key Facilitator of Cancer Invasion

“…However, over the past decade, it has become clear that tumours are a heterogeneous mixture of cells that differ in their genetic make-up and phenotypic behaviour (Merlo et al 2006;Gerlinger et al 2012;Basanta and Anderson 2013). As part of a recent study, currently in preparation for publication (Damaghi et al 2019), we observed significant heterogeneity in the distribution of matrix remodelling activity and acid adaptation among cancer cells in human breast cancer ducts ( Fig. 1).…”

“…A pathologist reviewer scored the intensity of each stain on a scale from 0 to 3, where a 0 was considered negative, score 1 was weakly positive, score 2 was moderately positive, and score 3 was strongly positive. For further information, see Damaghi et al (2019).…”

Mix & Match: Phenotypic coexistence as a key facilitator of solid tumour invasion

“…However, over the past decade it has become clear that tumours are a heterogeneous mixture of cells that differ in their genetic makeup and phenotypic behaviour [38,29,7]. As part of a recent study, currently in preparation for publication [17], we observed significant heterogeneity in the distribution of matrix remodelling activity and acid adaptation amongst cancer cells in human breast cancer ducts ( Figure 1). Even along the invasive front the overlap of the regions of acid production and matrix remodelling is not complete ( Figure 1B).…”

“…A pathologist reviewer scored the intensity of each stain on a scale from 0 to 3, where a 0 was considered negative, score 1 was weakly positive, score 2 was moderately positive and score 3 was strongly positive. For further information see [17].…”