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Mechanics of a multilayer epithelium instruct tumor architecture and function [adult]

ABSTRACT: Loss of normal tissue architecture is a hallmark of oncogenic transformation. Mechanical forces sculpt tissue architectures during morphogenesis. However, their origins and consequences during tumorigenesis remain elusive. In skin, premalignant basal cell carcinomas (BCCs) form ‘buds’, while invasive squamous cell carcinomas (SCC) initiate as ‘folds’. Using computational modeling, genetic manipulations and biophysical measurements, we identify the biophysical underpinnings and biological consequences of these tumor architectures. Cell proliferation and actomyosin contractility dominate tissue architectures in monolayer, but not multilayer epithelia. In stratified epidermis, softening and enhanced remodeling of the basement membrane (BM) promote tumor budding, while BM stiffening promotes folding. We show that additional key forces stem from progenitor cell stratification and differentiation Tumor-specific suprabasal stiffness gradients are generated as oncogenic lesions progress toward malignancy, which we computationally predict alter extensile tensions on the tumor BM. The pathophysiologic ramifications of this prediction are profound. Genetically decreasing BM stiffness elevates BM tensions in silico and potentiates invasive SCC progression in vivo. Our findings suggest that mechanical forces, exerted from above and below progenitors of multilayered epithelia, are integrally linked and function to shape premalignant tumor architectures and influence tumor progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE152487 | GEO | 2020/07/01

REPOSITORIES: GEO

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Mechanics of a multilayer epithelium instruct tumor architecture and function [E15]

Project description:Loss of normal tissue architecture is a hallmark of oncogenic transformation. Mechanical forces sculpt tissue architectures during morphogenesis. However, their origins and consequences during tumorigenesis remain elusive. In skin, premalignant basal cell carcinomas (BCCs) form ‘buds’, while invasive squamous cell carcinomas (SCC) initiate as ‘folds’. Using computational modeling, genetic manipulations and biophysical measurements, we identify the biophysical underpinnings and biological consequences of these tumor architectures. Cell proliferation and actomyosin contractility dominate tissue architectures in monolayer, but not multilayer epithelia. In stratified epidermis, softening and enhanced remodeling of the basement membrane (BM) promote tumor budding, while BM stiffening promotes folding. We show that additional key forces stem from progenitor cell stratification and differentiation Tumor-specific suprabasal stiffness gradients are generated as oncogenic lesions progress toward malignancy, which we computationally predict alter extensile tensions on the tumor BM. The pathophysiologic ramifications of this prediction are profound. Genetically decreasing BM stiffness elevates BM tensions in silico and potentiates invasive SCC progression in vivo. Our findings suggest that mechanical forces, exerted from above and below progenitors of multilayered epithelia, are integrally linked and function to shape premalignant tumor architectures and influence tumor progression.

2020-07-01 | GSE152486 | GEO

Profiling premalignant lesions in lung squamous cell carcinomas identifies mechanisms involved in stepwise carcinogenesis

Project description:Lung squamous cell carcinoma (SCC) is thought to arise from premalignant lesions in the airway epithelium, therefore studying these lesions is critical for understanding lung carcinogenesis. We performed RNA sequencing on laser-microdissected representative cell populations along the SCC pathological continuum of patient-matched normal basal cells, premalignant lesions, and tumor cells. We discovered transcriptomic changes and identified genomic pathways altered with initiation and progression of SCC within individual patients. We used immunofluorescent staining to confirm gene expression changes in premalignant lesions and tumor cells, including increased expression of SLC2A1, CEACAM5, and PTBP3 at the protein level and increased activation of MYC via nuclear translocation. Cytoband enrichment analysis revealed coordinated loss and gain of expression in chromosome 3p and 3q regions, respectively, during carcinogenesis. This is the first gene expression profiling of airway premalignant lesions with patient-matched samples that provides insight into the mechanisms of stepwise lung carcinogenesis. Profiling of mRNA expression in laser-microdissected normal airway basal cells, premalignant airway lesions, and lung SCC tumor cells by massively parallel RNA sequencing.

2014-07-03 | E-GEOD-49155 | biostudies-arrayexpress

Profiling premalignant lesions in lung squamous cell carcinomas identifies mechanisms involved in stepwise carcinogenesis

2014-07-03 | GSE49155 | GEO

Carcinoma-associated fibroblasts stimulate cancer cell invasion by mechanically remodeling the basement membrane

Project description:The first step in metastasis is dissemination of tumor cells into the surrounding tissue, or stroma. In carcinomas, cancers of epithelial origin, tumor cells must first breach the basement membrane (BM), a network that encapsulates the tumor. As tumor progresses, other cell types that reside in the stroma, such as carcinoma-associated fibroblasts (CAFs) accumulate around the tumor. Whether CAFs can help cancer cells to breach the BM remains an open question. Here we show that CAFs promote cancer cell invasion by physically remodeling the BM. Using a novel 3D in vitro model we observed that primary CAFs isolated from colon cancer patients stimulate cancer cell invasion through a native mesenteric BM. This stimulated invasion is the result of the physical presence of CAFs rather than an increased invasive potential of cancer cells. In the presence of CAFs, cancer cells can invade the BM in a matrix metalloproteinase-independent manner. Using live imaging, we found that CAFs actively pull and stretch the BM, leading to the formation of gaps through which cancer cells can migrate. Notably, CAF-mediated gap-widening is independent of proteolysis but relies on actomyosin contractility. We propose that CAFs exert mechanical forces that alter the organization and the physical properties of the BM, making it permissive for cancer cell invasion.

2017-09-18 | PXD003670 | Pride

Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated Pdl1 Expression: Stroma Cells

Project description:Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that bi-allelic inactivation of Lkb1 and Pten in the mouse lung led to SCC that recapitulated the histology, gene expression and microenvironment found in human disease. Lkb1/Pten-null (LP) tumors expressed the squamous markers Krt5, p63 and Sox2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. Sca1+/Ngfr+ fractions were enriched for tumor propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and Ngfr+ cells in human SCCs highly expressed Pdl1, suggesting a novel mechanism of immune escape for TPCs. We used microarrays to detail the gene expression profles among lung SCC tumor epitheial cell, lung ADC tumor epithelia cell and normal epithelial cells. Kras tumor stroma cells and LP tumor stroma cells were sorted by FACS, the cells were gated as EpCAM-/CD45+/CD31+

2014-01-24 | E-GEOD-54352 | biostudies-arrayexpress

Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated Pdl1 Expression: Epithelial Cells

Project description:Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that bi-allelic inactivation of Lkb1 and Pten in the mouse lung led to SCC that recapitulated the histology, gene expression and microenvironment found in human disease. Lkb1/Pten-null (LP) tumors expressed the squamous markers Krt5, p63 and Sox2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. Sca1+/Ngfr+ fractions were enriched for tumor propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and Ngfr+ cells in human SCCs highly expressed Pdl1, suggesting a novel mechanism of immune escape for TPCs. We used microarrays to detail the gene expression profles among lung SCC tumor epitheial cell, lung ADC tumor epithelia cell and normal epithelial cells. Normal EpCAM+, Kras tumor EpCAM+ and LP tumor EpCAM+ were sorted by FACS, the cells were gating as EpCAM+/CD45-/CD31-

2014-01-24 | E-GEOD-54351 | biostudies-arrayexpress

CSL RNA-Seq on HKC and SCC cell lines

Project description:Down-modulation or loss-of-function mutations of the Notch 1 and 2 genes are associated with development of squamous cell carcinoma (SCC), a very frequent and therapy-resilient malignancy in skin, head/neck (H/N), lung and other surface epithelia. In this context, surprisingly little is known on the role of CSL (RBP-Jk), key effector of canonical Notch signaling endowed with intrinsic transcription repressive function. CSL expression is decreased in upper epidermal layers and differentiating primary human keratinocytes (HKCs), while it is up-regulated in premalignant and malignant SCC lesions and SCC cell lines from skin, Head/Neck and lung. Increased CSL levels enhance proliferation and self-renewal potential of HKCs and SCC cells, while its silencing induces growth arrest and apoptosis. In vivo, SCC cells with increased CSL levels give rise to rapidly expanding tumors, while upon CSL silencing they form smaller and more differentiated tumors with enhanced inflammatory infiltrate. Global transcriptomic analysis of HKC and SCC cells plus/minus CSL silencing reveals major modulation of apoptotic, cell cycle and pro-inflammatory genes, with no significant association with Notch or keratinocyte differentiation gene signatures. KDM6B, a histone demethylase gene with highly context dependent functions, is a direct CSL negative target, with an inverse role of CSL in HKC and SCC self-renewal and tumorigenesis, with IL6 as a target of likely significance. CSL / KDM6B protein expression could be used as biomarkers of SCC development and novel indicators of cancer treatment.

2017-12-15 | GSE102762 | GEO

CSL ChIP-Seq on human keratinocytes

2017-12-15 | GSE102761 | GEO

Identification of a human airway epithelial cell subpopulation with altered biophysical, molecular, and metastatic properties

Project description:Lung cancers are documented to have remarkable intratumoral genetic heterogeneity. However, little is known about the heterogeneity of biophysical properties, such as cell motility, and its relationship to early disease pathogenesis and micrometastatic dissemination. In this study, we identified and selected a subpopulation of highly migratory premalignant pulmonary epithelial cells that were observed to migrate through microscale constrictions at up to 100-fold the rate of unselected cells. This enhanced migratory capacity was found to be Rac1-dependent and heritable, as evidenced by maintenance of the phenotype through multiple cell divisions continuing more than 8-weeks post-selection. The morphology of this lung epithelial subpopulation was characterized by increased cell protrusion intensity. In a murine model of micrometastatic seeding and pulmonary colonization, the motility-selected premalignant cells exhibit both enhanced survival in short term assays and enhanced outgrowth of premalignant lesions in longer term assays, thus overcoming important aspects of “metastatic inefficiency.” Overall, our findings indicate that among premalignant pulmonary epithelial cells, subpopulations with heritable motility-related biophysical properties exist, and these may explain micrometastatic seeding occurring early in the pathogenesis of lung cancer. Understanding, targeting, and preventing these critical biophysical traits and their underlying molecular mechanisms may provide a new approach to prevent metastatic behavior.

2017-06-28 | GSE100527 | GEO

Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated Pdl1 Expression: Stroma Cells

2014-01-24 | GSE54352 | GEO

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