Chromosomal instability as an architect of the cancer stemness landscape.

Despite a critical role for tumor-initiating cancer stem cells (CSCs) in breast cancer progression, major questions remain about the properties and signaling pathways essential for their function. Recent discoveries highlighting mechanisms of CSC-resistance to the stress caused by chromosomal instability (CIN) may provide valuable new insight into the underlying forces driving stemness properties. While stress tolerance is a well-known attribute of CSCs, CIN-induced stress is distinctive since levels appear to increase during tumor initiation and metastasis.

A dataset of chromosomal instability gene signature scores in normal and cancer cells from the human breast.

These data show the relative amount of chromosomal instability (CIN) in a diverse array of human breast cell types, including non-transformed mammary epithelial cells as well as cancer cell lines. Additional data is also provided from human embryonic and mesenchymal stem cells. To produce this dataset, we compared a published chromosomal instability gene signature against publicly available datasets containing gene expression information for each cell.

Breast cancer stem cells tolerate chromosomal instability during tumor progression via c-Jun/AXL stress signaling.

Chromosomal instability (CIN) is critical for tumor evolution, yet its relationship with stemness is unclear. Here, we describe CIN as a key stress induced during tumor initiation that is uniquely tolerated by breast cancer stem cells in an activated signaling state (aCSCs). While we noted elevated CIN specifically in tumors from aCSCs, this was not intrinsic to these cells, as baseline levels were similar to non-stem cell types.

Stem-like breast cancer cells in the activated state resist genetic stress via TGFBI-ZEB1.

Breast cancer cells with stem-like properties are critical for tumor progression, yet much about these cells remains unknown. Here, we characterize a population of stem-like breast cancer cells expressing the integrin αvβ3 as transcriptionally related to activated stem/basal cells in the normal human mammary gland. An unbiased functional screen of genes unique to these cells identified the matrix protein TGFBI (BIG-H3) and the transcription factor ZEB1 as necessary for tumorsphere formation.

Combined Bcl-2/Src inhibition synergize to deplete stem-like breast cancer cells.

Breast cancer cells with stem cell properties play an important role in tumor progression and thus are key targets for therapy. Here, we show that combined Bcl-2/Src inhibition synergize to deplete stem-like cells. While Src inhibition increases pro-apoptotic PUMA, we find that a significant amount interacts with Bcl-2 and Bcl-xL, promoting resistance to cell death.

Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasis.

Breast cancer cells with stem cell properties are key contributors to metastatic disease, and there remains a need to better understand and target these cells in human cancers. Here, we identified rare stem-like cells in patients' tumors characterized by low levels of the proapoptotic molecule p53-upregulated modulator of apoptosis (PUMA) and showed that these cells play a critical role in tumor progression that is independent of clinical subtype. A signaling axis consisting of the integrin αvβ3, Src kinase, and the transcription factor Slug suppresses PUMA in these cells, promoting tumor stemness.

Galectin-3, a Druggable Vulnerability for KRAS-Addicted Cancers.

Identifying the molecular basis for cancer cell dependence on oncogenes such as can provide new opportunities to target these addictions. Here, we identify a novel role for the carbohydrate-binding protein galectin-3 as a lynchpin for KRAS dependence. By directly binding to the cell surface receptor integrin αvβ3, galectin-3 gives rise to KRAS addiction by enabling multiple functions of KRAS in anchorage-independent cells, including formation of macropinosomes that facilitate nutrient uptake and ability to maintain redox balance.

Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance.

Interactions between cancer cells and their surroundings can trigger essential signaling cues that determine cell fate and influence the evolution of the malignant phenotype. As the primary receptors involved in cell-matrix adhesion, integrins present on the surface of tumor and stromal cells have a profound impact on the ability to survive in specific locations, but in some cases, these receptors can also function in the absence of ligand binding to promote stemness and survival in the presence of environmental and therapeutic stresses. Understanding how integrin expression and function is regulated in this context will enable the development of new therapeutic approaches to sensitize tumors to therapy and suppress their metastatic phenotype.

Integrin αvβ3 drives slug activation and stemness in the pregnant and neoplastic mammary gland.

Although integrin αvβ3 is linked to cancer progression, its role in epithelial development is unclear. Here, we show that αvβ3 plays a critical role in adult mammary stem cells (MaSCs) during pregnancy. Whereas αvβ3 is a luminal progenitor marker in the virgin gland, we noted increased αvβ3 expression in MaSCs at midpregnancy.

An integrin β₃-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition.

Tumour cells, with stem-like properties, are highly aggressive and often show drug resistance. Here, we reveal that integrin α(v)β₃ serves as a marker of breast, lung and pancreatic carcinomas with stem-like properties that are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. This was observed in vitro and in mice bearing patient-derived tumour xenografts or in clinical specimens from lung cancer patients who had progressed on erlotinib.

PI3Kα activates integrin α4β1 to establish a metastatic niche in lymph nodes.

Lymph nodes are initial sites of tumor metastasis, yet whether the lymph node microenvironment actively promotes tumor metastasis remains unknown. We show here that VEGF-C/PI3Kα-driven remodeling of lymph nodes promotes tumor metastasis by activating integrin α4β1 on lymph node lymphatic endothelium. Activated integrin α4β1 promotes expansion of the lymphatic endothelium in lymph nodes and serves as an adhesive ligand that captures vascular cell adhesion molecule 1 (VCAM-1)(+) metastatic tumor cells, thereby promoting lymph node metastasis.

EGFR-mediated carcinoma cell metastasis mediated by integrin αvβ5 depends on activation of c-Src and cleavage of MUC1.

Receptor tyrosine kinases and integrins play an essential role in tumor cell invasion and metastasis. We previously showed that EGF and other growth factors induce human carcinoma cell invasion and metastasis mediated by integrin αvβ5 that is prevented by Src blockade. MUC1, a transmembrane glycoprotein, is expressed in most epithelial tumors as a heterodimer consisting of an extracellular and a transmembrane subunit.

RBBP9: a tumor-associated serine hydrolase activity required for pancreatic neoplasia.

Pancreatic cancer is one of the most lethal malignancies. To discover functionally relevant modulators of pancreatic neoplasia, we performed activity-based proteomic profiling on primary human ductal adenocarcinomas. Here, we identify retinoblastoma-binding protein 9 (RBBP9) as a tumor-associated serine hydrolase that displays elevated activity in pancreatic carcinomas.

Integrins in cancer: biological implications and therapeutic opportunities.

The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumours. The importance of integrins in several cell types that affect tumour progression has made them an appealing target for cancer therapy. Integrin antagonists, including the alphavbeta3 and alphavbeta5 inhibitor cilengitide, have shown encouraging activity in Phase II clinical trials and cilengitide is currently being tested in a Phase III trial in patients with glioblastoma.

An integrin alpha(v)beta(3)-c-Src oncogenic unit promotes anchorage-independence and tumor progression.

Integrins regulate adhesion-dependent growth, survival and invasion of tumor cells. In particular, expression of integrin alpha(v)beta(3) is associated with progression of a variety of human tumors. Here we reveal a previously undescribed adhesion-independent role for integrin alpha(v)beta(3) in pancreatic cancer and other carcinomas.

Transforming growth factor beta regulates the expression of the M2 muscarinic receptor in atrial myocytes via an effect on RhoA and p190RhoGAP.

Transforming growth factor beta (TGFbeta) signaling is involved in the development and regulation of multiple organ systems and cellular signaling pathways. We recently demonstrated that TGFbeta regulates the response of atrial myocytes to parasympathetic stimulation. Here, TGFbeta(1) is shown to inhibit expression of the M(2) muscarinic receptor (M(2)), which plays a critical role in the parasympathetic response of the heart.

Activin receptor-like kinase 2 and Smad6 regulate epithelial-mesenchymal transformation during cardiac valve formation.

Epithelial-mesenchymal transformation (EMT) occurs during both development and tumorigenesis. Transforming growth factor beta (TGFbeta) ligands signal EMT in the atrioventricular (AV) cushion of the developing heart, a critical step in valve formation. TGFbeta signals through a complex of type I and type II receptors.

Early events in valvulogenesis: a signaling perspective.

The proper formation and function of the vertebrate heart requires a multitude of specific cell and tissue interactions. These interactions drive the early specification and assembly of components of the cardiovascular system that lead to a functioning system before the attainment of the definitive cardiac and vascular structures seen in the adult. Many of these adult structures are hypothesized to require both proper molecular and physical cues to form correctly.

Transforming growth factor beta (TGFbeta ) signaling via differential activation of activin receptor-like kinases 2 and 5 during cardiac development. Role in regulating parasympathetic responsiveness.

Little is known regarding factors that induce parasympathetic responsiveness during cardiac development. We demonstrated previously that in atrial cells cultured from chicks 14 days in ovo, transforming growth factor beta (TGFbeta) decreased parasympathetic inhibition of beat rate by the muscarinic agonist, carbamylcholine, by 5-fold and decreased expression of Galpha(i2). Here in atrial cells 5 days in ovo, TGFbeta increased carbamylcholine inhibition of beat rate 2.