HSET Overexpression Fuels Tumor Progression via Centrosome Clustering-Independent Mechanisms in Breast Cancer Patients

Human breast tumors harbor supernumerary centrosomes in almost 80% of tumor cells. Although amplified centrosomes compromise cell viability via multipolar spindles resulting in death-inducing aneuploidy, cancer cells tend to cluster extra centrosomes during mitosis. As a result cancer cells display bipolar spindle phenotypes to maintain a tolerable level of aneuploidy, an edge to their survival. HSET/KifC1, a kinesin-like minus-end directed microtubule motor has recently found fame as a crucial centrosome clustering molecule. Here we show that HSET promotes tumor progression via mechanisms independent of centrosome clustering. We found that HSET is overexpressed in breast carcinomas wherein nuclear HSET accumulation correlated with histological grade and predicted poor progression-free and overall survival. In addition, deregulated HSET protein expression was associated with gene amplification and/or translocation. Our data provide compelling evidence that HSET overexpression is pro-proliferative, promotes clonogenic-survival and enhances cellcycle kinetics through G2 and M-phases. Importantly, HSET co-immunoprecipitates with survivin, and its overexpression protects survivin from proteasome-mediated degradation, resulting in its increased steady-state levels. We provide the first evidence of centrosome clustering-independent activities of HSET that fuel tumor progression and firmly establish that HSET can serve both as a potential prognostic biomarker and as a valuable cancer-selective therapeutic target

The Role of Extracellular Matrix in Cancer Development and Progression

The extracellular matrix (ECM) scaffold, which surrounds and supports the cells in tissues, consists of fibrillar proteins, proteoglycans, glycosaminoglycans, signaling molecules, and enzymes involved in its remodeling. The stages of cancer progression, e.g., local invasion, intravasation, extravasation, distant invasion and immunosuppression, are obligatorily perpetrated through interactions of these tumor cells with the ECM. Cancer-related ECM changes can be exploited for the evaluation of disease progression, anticancer therapy development, and monitoring of therapy response. Thus, in breast cancer, hyaluronan-mediated wound repair mechanisms are hijacked to promote tumor development. Altered mechanical properties of the pancreatic cancer ECM are immunosuppressive and prevent the penetration of cytotoxic chemotherapy agents. The expression of the proteoglycan syndecan-4 is modulated by anticancer drugs, suggesting its potential druggabilty capacity. Another proteoglycan, lumican, is proposed as a cancer prognosis marker, chemoresistance regulator, and cancer therapy target. Due to their remodeling properties, the MMPs are vital mediators and important therapeutic targets. Treatment of breast cancer cells with sulfated hyaluronan has been shown to attenuate tumor cell growth, migration, and invasion. Extracellular vesicles (EVs), comprising exosomes, microvesicles, and apoptotic bodies, are released by all cells into the ECM and body fluids and can be utilized as diagnostic markers in malignant pleural mesothelioma. These exciting developments encourage tumor biology scientists for further creative research

Predictive and Prognosis Factors of Clinical Utility in Mesothelioma

The constant research in therapeutics for mesothelioma has been improving their tumor response and overall survival, generating the need to propose markers that guide the doctor’s therapeutic approach in a more precise way. Recently, different predictive factors have been proposed, such as mesothelin-related peptides, fibulin-3, and osteopontin associated with an image giving information about the probability of tumor response to a therapeutic agent or a combination of agents. As is well known, the importance of prognostic markers of utility lies in providing prospective information on the evolution of the patient and thus their ability to guide therapeutic decisions. Although the clinical stage and histology are currently the most described prognostic factors, recent studies have shown interest in the expression of estrogen receptor beta and calretinin, among other promising factors. Given the heterogeneity of this broad field of research in mesothelioma, it is necessary to objectively present the prognostic and predictive factors of greater clinical utility

Liver Tumors

This book is oriented towards clinicians and scientists in the field of the management of patients with liver tumors. As many unresolved problems regarding primary and metastatic liver cancer still await investigation, I hope this book can serve as a tiny step on a long way that we need to run on the battlefield of liver tumors

Personalized cancer medicine guided by liquid biopsies

The capacity to optimally treat cancer patients is nowadays challenged by several factors. These challenges are particularly caused by tumor heterogeneity and plasticity, causing tumor characteristics to change over time and under treatment pressure. The use of liquid biopsies sampled from the blood of patients with cancer is a promising way to evaluate tumor characteristics and response to therapy repeatedly during therapy. In the long run, the availability of these sort of biomarkers which can tailor the right therapeutic strategy, for the right person, at the right time, is where we can use knowledge on the biology of cancer to treat ca

Conduits of Intratumor Heterogeneity: Centrosome Amplification, Centrosome Clustering and Mitotic Frequency

Tumor initiation and progression is dependent on the acquisition and accumulation of multiple driver mutations that acti­vate and fuel oncogenic pathways and deactivate tumor suppressor networks. This complex continuum of non-stochastic genetic changes in accompaniment with error-prone mitoses largely explains why tumors are a mosaic of different cells. Contrary to the long-held notion that tumors are dominated by genetically-identical cells, tumors often contain many different subsets of cells that are remarkably diverse and distinct. The extent of this intratumor heterogeneity has bewildered cancer biologists’ and clinicians alike, as this partly illuminates why most cancer treatments fail. Unsurprisingly, there is no “wonder” drug yet available which can target all the different sub-populations including rare clones, and conquer the war on cancer. Breast tumors harbor ginormous extent of intratumoral heterogeneity, both within primary and metastatic lesions. This revelation essentially calls into question mega clinical endeavors such as the Human Genome Project that have sequenced a single biopsy from a large tumor mass thus precluding realization of the fact that a single tumor mass comprises of cells that present a variety of flavors in genotypic compositions. It is also becoming recognized that intratumor clonal heterogeneity underlies therapeutic resistance. Thus to comprehend the clinical behavior and therapeutic management of tumors, it is imperative to recognize and understand how intratumor heterogeneity arises. To this end, my research proposes to study two main features/cellular traits of tumors that can be quantitatively evaluated as “surrogates” to represent tumor heterogeneity at various stages of the disease: (a) centrosome amplification and clustering, and (b) mitotic frequency. This study aims at interrogating how a collaborative interplay of these “vehicles” support the tumor’s evolutionary agenda, and how we can glean prognostic and predictive information from an accurate determination of these cellular traits