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High collagen density augments mTOR-dependent cancer stem cells in ER?+ mammary carcinomas, and increases mTOR-independent lung metastases.

ABSTRACT: Metastatic estrogen receptor alpha positive (ER?+) cancers account for most breast cancer mortality. Cancer stem cells (CSCs) and dense/stiff extracellular matrices are implicated in aggression and therapy resistance. We examined this interplay and response to mTOR inhibition using ER?+ adenocarcinomas from NRL-PRL females in combination with Col1a1tmJae/+ (mCol1a1) mice, which accumulate collagen-I around growing tumors. Orthotopic transplantation of tumor cells to mCol1a1 but not wildtype hosts resulted in striking desmoplasia. Mammary tumors in mCol1a1 recipients displayed higher CSC activity and enhanced AKT-mTOR and YAP activation, and these animals developed more and larger lung metastases. Treatment with the mTOR inhibitor, rapamycin, with or without the anti-estrogen, ICI182780, rapidly diminished mammary tumors, which rapidly reversed when treatment ceased. In contrast, lung metastases, which exhibited lower proliferation and pS6RP, indicating lower mTOR activity, were unresponsive, and mCol1a1 hosts continued to sustain greater metastatic burdens. These findings shed light on the influence of desmoplastic tumor microenvironments on the CSC niche and metastatic behavior in ER?+ breast cancer. The differential mTOR dependence of local mammary tumors and pulmonary lesions has implications for success of mTOR inhibitors in advanced ER?+ disease.

SUBMITTER: Shea MP

PROVIDER: S-EPMC6064659 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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High collagen density augments mTOR-dependent cancer stem cells in ERα+ mammary carcinomas, and increases mTOR-independent lung metastases.

Shea Michael P MP O'Leary Kathleen A KA Wegner Kyle A KA Vezina Chad M CM Schuler Linda A LA

Cancer letters 20180620

Metastatic estrogen receptor alpha positive (ERα+) cancers account for most breast cancer mortality. Cancer stem cells (CSCs) and dense/stiff extracellular matrices are implicated in aggression and therapy resistance. We examined this interplay and response to mTOR inhibition using ERα+ adenocarcinomas from NRL-PRL females in combination with Col1a1<sup>tmJae/+</sup> (mCol1a1) mice, which accumulate collagen-I around growing tumors. Orthotopic transplantation of tumor cells to mCol1a1 but not wi ...[more]

PMID: 29935374

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Project description:Mammographically dense breast tissue is one of the greatest risk factors for developing breast carcinoma. Despite the strong clinical correlation, breast density has not been causally linked to tumorigenesis, largely because no animal model has existed for studying breast tissue density. Importantly, regions of high breast density are associated with increased stromal collagen. Thus, the influence of the extracellular matrix on breast carcinoma development and the underlying molecular mechanisms are not understood.To study the effects of collagen density on mammary tumor formation and progression, we utilized a bi-transgenic tumor model with increased stromal collagen in mouse mammary tissue. Imaging of the tumors and tumor-stromal interface in live tumor tissue was performed with multiphoton laser-scanning microscopy to generate multiphoton excitation and spectrally resolved fluorescent lifetimes of endogenous fluorophores. Second harmonic generation was utilized to image stromal collagen.Herein we demonstrate that increased stromal collagen in mouse mammary tissue significantly increases tumor formation approximately three-fold (p < 0.00001) and results in a significantly more invasive phenotype with approximately three times more lung metastasis (p < 0.05). Furthermore, the increased invasive phenotype of tumor cells that arose within collagen-dense mammary tissues remains after tumor explants are cultured within reconstituted three-dimensional collagen gels. To better understand this behavior we imaged live tumors using nonlinear optical imaging approaches to demonstrate that local invasion is facilitated by stromal collagen re-organization and that this behavior is significantly increased in collagen-dense tissues. In addition, using multiphoton fluorescence and spectral lifetime imaging we identify a metabolic signature for flavin adenine dinucleotide, with increased fluorescent intensity and lifetime, in invading metastatic cells.This study provides the first data causally linking increased stromal collagen to mammary tumor formation and metastasis, and demonstrates that fundamental differences arise and persist in epithelial tumor cells that progressed within collagen-dense microenvironments. Furthermore, the imaging techniques and signature identified in this work may provide useful diagnostic tools to rapidly assess fresh tissue biopsies.

Dataset Information

High collagen density augments mTOR-dependent cancer stem cells in ER?+ mammary carcinomas, and increases mTOR-independent lung metastases.

Publications

High collagen density augments mTOR-dependent cancer stem cells in ERα+ mammary carcinomas, and increases mTOR-independent lung metastases.

Similar Datasets

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