Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness

Abstract

Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.

Study of breast cancer incidence in patients of lymphangioleiomyomatosis

“…In previous analyses, we tested the hypothesis that the metastatic properties of LAM cells could be further depicted using knowledge of breast cancer tropism to lung, and thus identified the expression of metastatic mediators and cancer cell stemness molecular determinants in LAM lesions [ 8 ]. Following on from this evidence, and given that the tissue of origin of LAM cells remains a subject of debate [ 3 , 18 , 19 ], we aimed to assess breast cancer incidence in LAM patients.…”

“…These observations led us to the test whether the mediators of breast cancer metastasis to lung could also play a role in LAM. Thus, we identified molecular positivity in LAM lesions for known metastasis mediators [ 8 ]. Low TSC1/2 expression in primary breast tumors was found to be associated with enhanced mTORC1 signaling and lung (but not bone) metastasis.…”

Fascin induces melanoma tumorigenesis and stemness through regulating the Hippo pathway

“…It is generally thought that the causal role of fascin in tumor metastasis predominantly depends on its actin-bundling activity. A number of recent studies demonstrated that fascin is a key regulator of mammary tumorigenesis and breast cancer cell stemness [ 6 , 7 ]. However, its role in melanoma tumorigenesis and melanoma metastasis remains largely unknown.…”

Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition

“… 8 Thus, therapies that combine allosteric inhibitors (rapamycin (sirolimus) and rapalogs) with inhibitors of growth factor signaling have been extensively evaluated. 9 Intriguingly, recent studies have further linked mTOR activity to a stem cell-like cancer phenotype that mediates breast cancer metastasis 10 , 11 and, using triple-negative (TN) breast cancer cell lines, have described that mTORC1/2 inhibition spares a cell population with stem cell-like properties and enhanced NOTCH activity. 12 These results are consistent with previous observations concerning the required activation of mTOR signaling in breast cancer stem-like viability and maintenance, 13 the enhancement of NOTCH signaling in poorly differentiated breast tumors 14 and the increase of tumor-initiating capacities with mTOR inhibition in liver cancer.…”